Use of pridopidine for treating dystonias

ABSTRACT

The invention provides a method of treating a subject afflicted with a dystonia, comprising periodically administering to the subject a pharmaceutical composition comprising an amount of pridopidine effective to treat the subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part Application fromPCT/US2017/048458 filed 24 Aug. 2017, which claims the benefit of U.S.Provisional Application No. 62/395,319, filed Sep. 15, 2016 and U.S.Provisional Application No. 62/379,175, filed Aug. 24, 2016, thecontents of each of which are hereby incorporated by reference in theirentirety.

Throughout this application, various publications are referred to byfirst author and year of publication. Full citations for thesepublications are presented in a References section immediately beforethe claims. Disclosures of the publications cited in the Referencessection are hereby incorporated by reference in their entireties intothis application in order to more fully describe the state of the art asof the date of the invention described herein.

FIELD OF THE INVENTION

The invention provides a method of treating a subject afflicted with adystonia, comprising periodically administering to the subject apharmaceutical composition comprising an amount of pridopidine effectiveto treat the subject.

BACKGROUND OF INVENTION

Dystonias

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions of agonist and antagonist musclescausing abnormal, often repetitive movements, postures, or both.Dystonic movements are typically patterned, twisting, and may betremulous. Dystonia is often initiated or worsened by voluntary actionand associated with overflow muscle activation. Dystonia is classifiedalong two axes: clinical characteristics, including age at onset, bodydistribution, temporal pattern and associated features (additionalmovement disorders or neurological features), and etiology, whichincludes nervous system pathology and inheritance (Albanese 2013a).

Dystonia is a dynamic condition that often changes in severity dependingon the posture assumed and on voluntary activity of the involved bodyarea. Symptoms may progress into adjacent muscles and vary according tothe type and location of the dystonia. Patients with dystonia mayexperience muscle spasms, cramping, pain, impaired vision (eyelidclosure), chewing, speech, or swallowing, loss of coordination, andabnormal posture/gait. This feature of dystonia has challenged thedevelopment of rating scales with acceptable clinimetric properties.(Albanese 2013a).

The clinical characteristics of dystonia include: age at onset (frominfancy to late adulthood), body distribution (focal, segmental or,generalized), and temporal pattern (static or progressive andvariability related to voluntary actions or to diurnal fluctuations).Dystonia can be isolated or combined with another movement disorder,such as parkinsonism or myoclonus, or can be associated with otherneurological or systemic manifestations. Isolated dystonia with onset inchildhood tends to progress to generalization, whereas dystonia arisingin adulthood usually remains focal or segmental.

Despite the identification of genetic mutations associated withdystonias, there remains uncertainty regarding the causative role ofthose gene variants. Many familial dystonia cases and the majority ofsporadic dystonia cases cannot be explained by validated mutations inknown dystonia gene. A list of genes for monogenic forms of isolated andcombined dystonias is presented in Table 1 of Verbeek and Gasser.(Verbeek 2017). Additional genes responsible for inherited dystonias arelisted in Albanese. (Albanese 2013a).

The classification of dystonia has evolved over time. The changingsystem for categorizing dystonia reflects, in part, an increasedunderstanding of the various clinical manifestations and etiologies, butalso the varied opinion on the merits and criteria for grouping certaindisorders together. (Albanese 2013a).

The most common hereditary, primary dystonia is DYT1 dystonia caused bya genetic mutation (DYT1) which results in a defect in an ATP-bindingprotein called Torsin A. Torsin A is expressed at high levels inneuronal cytoplasm of specific neuronal populations in the adult humanbrain, including the substantia nigra (SN), thalamus, cerebellum,hippocampus, and neostriatum. The defective Torsin A protein creates adisruption in communication in neurons that control muscle movement andmuscle control (Ozelius 1997; Albanese 2006).

The most common symptoms of DYT1 dystonia are dystonic musclecontractions causing posturing of a foot, leg, or arm. Dystonia isusually first apparent with specific actions such as writing or walking.Over time, the contractions frequently (but not invariably) becomeevident with less specific actions and spread to other body regions. Noother neurologic abnormalities are present, except for postural armtremor. Disease severity varies considerably even within the samefamily. Isolated writer's cramp may be the only sign (Ozelius 1999).

In most instances, DYT1 dystonia symptoms start with a focal dystonia astalipes equinovarus of one leg in early childhood, typically around 6years of age. The dystonic posturing then gradually progresses with ageto other extremities and trunk muscles by the early teens. Dystonia mayalso start in an arm. There is asymmetry to the dystonia, withinvolvement of the extremities on the dominant side along with theipsilateral sternocleidomastoid muscle. In these patients, interlimbcoordination and locomotive movements are not affected. Moreover,intellectual, mental, and psychological functions are completely intactin these patients (Ozelius 1997; Ozelius 1999; Albanese 2006).

Based on clinical characteristics, it has been proposed that DYT1dystonia can be classified into two types: the postural type withappendicular and truncal dystonias, or the action type, which isassociated with violent dyskinetic movements in addition to dystonicposture (Segawa 2014).

Pridopidine

Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) (formerlyknown as ACR16) is a drug under development for treatment ofHuntington's disease. Pridopidine has been shown to modulate motoractivity by either suppressing hyperactivity or enhancing hypoactivity.The neuroprotective properties of pridopidine are suggested to beattributed to its high affinity to the Sigma-1 receptor (S1R, bindingIC50˜100 nM), while the motor activity of pridopidine may be mediatedprimarily by its low-affinity, antagonistic activity at the dopamine D2receptor (D2R) (binding IC50˜10 μM) (Ponten 2010). Pridopidine showslow-affinity binding to additional receptors in the micromolar range.

The S1R is an endoplasmic reticulum (ER) chaperone protein which isimplicated in cellular differentiation, neuroplasticity, neuroprotectionand cognitive function in the brain. Recently, transcriptomic analysisof rat striatum showed that pridopidine treatment activates expressionof the BDNF, dopamine receptor 1 (D1R), glucocorticoid receptor (GR),and the serine-threonine kinase protein kinase B (Akt)/phosphoinositide3-kinase (PI3K) pathways, known to promote neuronal plasticity andsurvival and to be impaired in HD. Moreover, pridopidine gene expressionprofile showed a reversed pattern of the HD disease gene expressionprofile in a Q175 knock-in (Q175 KI) HD mouse model (Geva 2016).Pridopidine also enhances secretion of the neuroprotective brain-derivedneurotrophic factor (BDNF) in a neuroblastoma cell line, in aS1R-dependent manner (Geva 2016).

BRIEF SUMMARY OF THE INVENTION

This invention provides a method of treating a subject afflicted with adystonia, comprising periodically administering to the subject apharmaceutical composition comprising an amount of pridopidine effectiveto treat the subject.

This invention provides a method of treating a subject afflicted with adystonia comprising periodically administering to the subject apharmaceutical composition comprising an amount of pridopidine or itspharmaceutically acceptable salt, effective to treat the subject,wherein the dystonia is a primary dystonia, an isolated dystonia, anearly onset generalized dystonia, a secondary dystonia, a focaldystonia, a segmental dystonia, a multifocal dystonia, a hemidystonia, ageneralized dystonia, paroxysmal dystonia, Blepharospasm (BenignEssential Blepharospasm[BEB]), Cervical Dystonia (SpasmodicTorticollis[ST]), Acquired Dystonia, Oromandibular Dystonia, Embouchuredystonia, Paroxysmal Dystonia Choreoathetosis, Paroxysmal nonkinesigenicdyskinesia (PKND), Spasmodic Dysphonia (SD), Spasmodic Torticollis(Cervical Dystonia), Tardive Dystonia, writer's Cramp dystonia or anycombination thereof.

This invention further provides a method of treating a subject afflictedwith a dystonia as a symptom of a disorder comprising: Huntingtondisease, Parkinson disease, Alzheimer disease, Wilson's disease,Multiple Sclerosis, birth injury, disorders that develop in some peoplewith cancer (paraneoplastic syndromes), oxygen deprivation or carbonmonoxide poisoning, infections such as HIV, tuberculosis orencephalitis, reactions to certain medications or heavy metal poisoning,comprising periodically administering to the subject a pharmaceuticalcomposition comprising an amount of pridopidine or its pharmaceuticallyacceptable salt effective to treat the subject or a genetic dystonias.

The invention also provides pridopidine for the manufacture of amedicament for use in treating a subject afflicted with a dystonia.

The invention also provides a pharmaceutical composition comprising aneffective amount of pridopidine for treating a dystonia.

The invention also provides a pharmaceutical composition comprisingpridopidine for use in treating a subject suffering from a dystonia.

The invention also provides a package comprising:

-   -   a) a pharmaceutical composition comprising an amount of        pridopidine; and    -   b) instructions for use of the pharmaceutical composition to        treat a subject afflicted with a dystonia.

The invention also provides a therapeutic package for dispensing to, orfor use in dispensing to, a subject afflicted with a dystonia, whichcomprises:

-   -   a) one or more unit doses, each such unit dose comprising an        amount of pridopidine thereof, wherein the amount of said        pridopidine in said unit dose is effective, upon administration        to said subject, to treat the subject, and    -   b) a finished pharmaceutical container therefor, said container        containing said unit dose or unit doses, said container further        containing or comprising labeling directing the use of said        package in the treatment of said subject.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The present invention is further illustrated by reference to theaccompanying drawings. In the following brief descriptions of thefigures and the corresponding figures, efficacy was assessed throughoutthe 52-week period using Mixed Models Repeated Measures (MMRM) analysesof change from baseline in the Unified Huntington's Disease Rating ScaleTotal Motor Score (UHDRS TMS; TMS), the modified Physical PerformanceTest (mPPT), individual TMS subscales, functional, cognitive and otheroutcomes.

FIG. 1 : Pridopidine concentration in patient's blood (ng/mL; Mean(+/'sd) measured values). “Pre” means predose and “post” mean post dose.V2 means visit 2, V3 means visit 3, etc. Wk2 means second week, Wk3means third week, etc.

FIG. 2 : Pridopidine concentration in patient's blood (ng/mL). Post-dose(“Cmax”) (+/−sd) at Steady State.

For FIGS. 1 and 2 , a % coefficient of variation (CV) of around 40% formeasured values is considered adequate for this setting [1-2 hours postdose, patient population, sparse sampling]. Variability is expected todecrease once true sampling times are taken into consideration.

FIG. 3 : Total Motor Score (TMS) Change from Baseline (BL) withpridopidine administration. The 90 mg bid dose (circles) demonstratedthe largest treatment effect. A decrease in TMS indicates animprovement. Table 1 below shows the P-Values corresponding to FIG. 3 .

TABLE 1 Week 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid 4 0.03040.0004 <.0001 <.0001 8 <.0001 <.0001 <.0001 <.0001 12 0.0002 0.0003<.0001 0.0002 16 <.0001 <.0001 <.0001 <.0001 20 <.0001 <.0001 <.0001<.0001 26 0.0013 0.0024 <.0001 0.0063

FIG. 4 : Total Motor Score (TMS)—Change from Baseline (90 mg pridopidinebid vs historical placebo in HART and MermaiHD clinical trials). Thereis about a 6.5 TMS point difference at week 26.

FIGS. 5 a and 5 b : Change from baseline in TMS. FIG. 5 a : Usinghistorical placebo in HART and MermaiHD clinical trials, TMS (changefrom baseline) results are significant for both 45 mg pridopidine bidand 90 mg pridopidine bid. A lower number indicates improvement. FIG. 5b : Change from baseline UHDRS-TMS full analysis set plotted over time.PRIDE-HD replicates previous data in TMS changes from baseline as thechange from baseline values were similar to those in HART and MermaiHD.In this graph, a decrease in TMS change from baseline indicatesimprovement. Dark line with diamonds represents placebo, dark line withopen circles represents 45 mg bid, gray line with triangles represents67.5 mg bid, gray line with diamonds represents 90 mg bid, line withsquares represents 112.5 mg bid. The 90 mg bid dose demonstrated thelargest treatment effect.

FIGS. 6 a, 6 b and 6 c : Total Dystonia at week 12 (6 a); at week 20 (6b); and at week 26 (6 c) in patient groups administered different dosesof pridopidine. Y-axis is change in dystonia from baseline. All datarefer to adjusted means+SE of change in dystonia in full analysis set. Alower number indicates improvement.

FIG. 7 a : Change in Dystonia in limbs (UHDRS-dystonia limbs) at week12; FIG. 7 b : Finger Taps and Pronate-Supinate (P/S) hands at week 20;FIG. 7 c : Finger Taps and P/S hands at week 26. Finger Taps andPronate-Supinate (P/S) hands is a combination of finger tapping (theability to tap the fingers of both hands where 15 repetitions in 5seconds is considered normal) with pronation/supination (the ability torotate the forearm and hand such that the palm is down (pronation) andto rotate the forearm and hand such that the palm is up (supination) onboth sides of the body).

In the tables below, data and the P-Values corresponding to the figuresare provided. N refers to number of patients. Wk26 refers to relevantscore at week 26. Wk52 refers to relevant score at week 52. “Δ toplacebo” refers to the difference in score from compared to placebo,specifically, the average change from baseline in the placebo groupcompared to the average change from baseline of the relevant group.“ALL” refers to pridopidine treated patients irrespective of diseasestage. Y-axes are change from baseline for characteristic listed abovethe table. X-axes are dose whereby P means “placebo”, 45 means “45 mgbid,” 67.5 means “67.5 mg bid,” 90 means “90 mg bid,” and 112.5 means“112.5 mg bid.” In the figures, improvement is in the direction frombottom of the graph to top of the graph.

For example, FIG. 8 b shows the average difference in the UHDRS TMSscore of the indicated group of patients (i.e. patients having a TFCscore of 11-13 at baseline) between the score at baseline (prior toadministration of pridopidine at week 0) and the score after 26 weeks ofadministration of pridopidine (at week 26). In this figure, the 90 mgbid dose shows the greatest improvement because its data point is thetop most data point in the figure, showing an approximately 8 pointimprovement compared to baseline (i.e. a −8 UHDRS TMS score at week 26compared to baseline). The table below the description of FIG. 8 b showsthat the 90 mg bid group had 11 patients (“N” row) and an average UHDRSTMS score of 39.1 at baseline (“Baseline” row). The table below thedescription of FIG. 8 b also shows that the 90 mg bid group's changefrom baseline (about −8, shown in figure, not shown in table) is 6.15points better (−6.15) than the placebo group's change from placebo(about −2, shown in figure, not shown in table)(“Δ to placebo” row).Additionally, the table below the description of FIG. 8 b shows a pvalue of 0.0361 for the 90 mg bid group (“p value” row). HD1 refers toan early stage Huntington's disease (HD) patient with a baseline UnifiedHuntington's Disease Rating Scale Total Functional Capacity (UHDRS-TFC;TFC) score of 11-13. HD2 refers to an early stage HD patient with abaseline UHDRS-TFC score of 7-10.

FIG. 8 a : Change from baseline in UHDRS TMS Week 26 ALL. The tablebelow and FIG. 8 a show no significant improvement in UHDRS TMS in allpridopidine treated patients at 26 weeks compared to placebo.Improvement is evidenced by a more negative value in the UHDRS TMSscore.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 46.9 44.5 46.9 47 46.7 Δ to 1.42 1.71 0.67 2.1 placebo p value0.3199 0.2235 0.6282 0.1337

FIG. 8 b : Change from baseline in UHDRS TMS Week 26 Stage 1 BL TFC11-13. (The UHDRS TMS score at week 26 of pridopidine treated patientswith a baseline Total Functional Capacity (BL TFC) score of 11 to 13).HD patients with a baseline TFC score of 11-13 are generally consideredto be first stage (stage 1) HD patients. The table below and FIG. 8 bshow trend towards improvement in UHDRS TMS in HD1 pridopidine treatedpatients at 26 weeks compared to placebo.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 37.3 35.4 36.4 39.1 38.7 Δ to −4.47 −3 −6.15 −4.79 placebo pvalue 0.0976 0.2505 0.0361 0.0676

FIG. 8 c : Change from baseline in UHDRS TMS Week 52 ALL. The tablebelow and FIG. 8 c show no significant improvement in UHDRS TMS in allpridopidine treated patients at 52 weeks, compared to placebo.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 46.9 44.5 46.9 47 46.7 Δ to 0.59 2.55 1.78 2.71 placebo p value0.7468 0.1591 0.3144 0.137

FIG. 8 d : Change from baseline in UHDRS TMS Week 52 Stage 1 BL TFC11-13. The table below and FIG. 8 d show a trend towards improvement inUHDRS TMS in HD1 pridopidine treated patients at 52 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 37.3 35.4 36.4 39.1 38.7 Wk 52 Δ −5.32 −0.84 −7.1 −0.92 toplacebo p value 0.1065 0.7918 0.047 0.7765

FIG. 8 e : Change from baseline in UHDRS TMS Gait and Balances Week 52.The table below and FIG. 8 e show no significant improvement in UHDRSTMS gait and balances in all pridopidine treated patients at 52 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 3.8 4.1 4.1 4 3.8 Δ to −0.09 −0.05 −0.01 0.04 placebo p value0.7404 0.8532 0.9747 0.8923

FIG. 8 f : Change from baseline in UHDRS TMS Gait and Balances Week 52Stage 1 BL TFC 11-13. The table below and FIG. 8 f show a trend towardsimprovement in UHDRS TMS gait and balances in HD1 pridopidine treatedpatients at 52 weeks with significance for patients receiving 45 mg bidpridopidine.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 2.3 2.8 2.6 2.6 2.4 Δ to −0.94 −0.53 −0.49 −0.4 placebo p value0.0445 0.2294 0.3056 0.3797

FIG. 8 g : Change from baseline in UHDRS TMS Chorea Week 26 ALL. Thetable below and FIG. 8 g show no significant improvement in UHDRS TMSchorea in all pridopidine treated patients at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 11.4 10.9 11 11.2 10.9 Δ to 0.92 0.81 0.36 1.05 placebo p value0.1083 0.1501 0.5185 0.0609

FIG. 8 h : Change from baseline in UHDRS TMS Chorea Week 26 Stage 1 BLTFC 11-13. The table below and FIG. 8 h show a trend towards improvementin UHDRS TMS chorea in HD1 pridopidine treated patients at 26 weeks withsignificance for patients receiving 90 mg bid pridopidine.

45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 17 17 11 18 Wk 26 Δ −1.4−2.07 −2.52 −1.08 to placebo p value 0.1805 0.0438 0.0271 0.2932

FIG. 8 i : Change from baseline in UHDRS TMS Dystonia Week 26 ALL. Thetable below and FIG. 8 i show a trend towards improvement in UHDRS TMSdystonia in all pridopidine treated patients at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 4.1 3.6 4.1 4.9 4.5 Δ to −0.06 −0.34 −0.33 −0.29 placebo pvalue 0.8711 0.3778 0.3845 0.4507

FIG. 8 j : Change from baseline in UHDRS TMS Dystonia Week 26 Stage 1 BLTFC 11-13. The table below and FIG. 8 j show a trend towards improvementin UHDRS TMS dystonia in HD1 pridopidine treated patients at 26 weekswith significance for patients receiving 90 mg bid pridopidine.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 2.8 2.1 2.2 3.2 2.4 Δ to −0.99 −0.89 −1.56 −0.53 placebo pvalue 0.1569 0.1882 0.0396 0.4303

FIG. 8 k : Change from baseline in UHDRS TMS Dystonia Week 52. The tablebelow and FIG. 8 k show a trend toward improvement in UHDRS TMS dystoniain all pridopidine treated patients at 52 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 4.1 3.6 4.1 4.9 4.5 Δ to −0.39 −0.35 −0.27 −0.24 placebo pvalue 0.4358 0.4795 0.5858 0.6382

FIG. 8 l : Change from baseline in UHDRS TMS Dystonia Week 52 Stage 1 BLTFC 11-13. The table below and FIG. 8 l show a trend towards improvementin UHDRS TMS dystonia in HD1 pridopidine treated patients at 52 weekswith significance for patients receiving 45 mg bid pridopidine.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 2.8 2.1 2.2 3.2 2.4 Δ to −1.65 −0.1 −1.46 −0.46 placebo p value0.0243 0.8848 0.0575 0.5228

FIG. 8 m : Change from baseline in UHDRS TMS Involuntary Movements Week26 ALL The table below and FIG. 8 m show no significant improvement inUHDRS TMS Involuntary Movements in all pridopidine treated patients at26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 15.6 14.4 15.1 16 15.4 Δ to 0.89 0.48 0.01 0.76 placebo p value0.2594 0.5328 0.9873 0.3268

FIG. 8 n : Change from baseline in UHDRS TMS Involuntary Movements Week26 Stage 1 BL TFC 11-13. The table below and FIG. 8 n show significantimprovement in UHDRS TMS Involuntary Movements at 26 weeks in HD1pridopidine treated patients receiving 45 mg bid, 67.5 bid and 90 mg bidpridopidine.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 11.5 12 12.2 12.9 13.2 Δ to −2.49 −3.07 −4 −1.64 placebo pvalue 0.0469 0.0117 0.0033 0.1731

FIG. 8 o : Change from baseline in UHDRS TMS Involuntary Movements Week52 The table below and FIG. 8 o show no significant improvement in UHDRSTMS Involuntary Movements in all pridopidine treated patients at 52weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 15.6 14.4 15.1 16 15.4 Δ to 0.02 0.8 −0.26 0.57 placebo p value0.9867 0.4196 0.7893 0.5648

FIG. 8 p : Change from baseline in UHDRS TMS Involuntary Movements Week52 Stage 1 BL TFC 11-13. The table below and FIG. 8 p show a trendtowards improvement in UHDRS TMS Involuntary Movements in HD1pridopidine treated patients at 52 weeks, in particular in 45 mg bid and90 mg bid treated patients.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 11.5 12 12.2 12.9 13.2 Δ to −2.73 −0.2 −3.8 0.8 placebo p value0.1487 0.9111 0.0643 0.6751

FIG. 8 q : Change from baseline in UHDRS TMS Excluding Chorea Week 52.The table below and FIG. 8 q show no significant improvement in UHDRSTMS excluding chorea in all pridopidine treated patients at 52 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 35.5 33.6 35.9 35.8 35.8 Δ to 0.05 1.31 1.67 1.94 placebo pvalue 0.9693 0.3495 0.2234 0.1704

FIG. 8 r : Change from baseline in UHDRS TMS Excluding Chorea Week 52Stage 1 BL TFC 11-13. The table below and FIG. 8 r show a trend towardsimprovement in UHDRS TMS excluding chorea in HD1 pridopidine treatedpatients at 52 weeks, in particular in the 45 mg bid and 90 mg bidtreated patients.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 28.6 25.5 26.4 29.4 27.8 Δ to −4.09 −0.18 −4.92 −1.59 placebo pvalue 0.083 0.9358 0.0505 0.4924

FIG. 8 s : Change from baseline in UHDRS TMS Excluding Dystonia Week 26ALL. The table below and FIG. 8 s show no significant improvement inUHDRS TMS excluding dystonia in all pridopidine treated patients at 26weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 42.7 40.9 42.8 42.1 42.2 Δ to 1.39 1.97 1.2 2.4 placebo p value0.2733 0.1137 0.3314 0.0539

FIG. 8 t : Change from baseline in UHDRS TMS Excluding Dystonia Week 26Stage 1 BL TFC 11-13. The table below and FIG. 8 t show a trend towardsimprovement in UHDRS TMS excluding dystonia in HD1 pridopidine treatedpatients, at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 12 17 17 11 18Baseline 34.6 33.4 34.1 35.9 36.3 Δ to −3.6 −2.2 −4.35 −4.31 placebo pvalue 0.1594 0.376 0.1167 0.0842

FIGS. 9 a-9 e show bar graphs of changes in UHDRS TMS Finger Tap scoresin 26 and 52 week patient groups.

FIG. 9 a : Change from Baseline in UHDRS TMS Finger Taps ALL. Week 26.The table below provides P-Values corresponding to FIG. 9 a . The tablebelow and FIG. 9 a show no significant improvement in the UHDRS TMSfinger taps in all pridopidine treated patients, at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 3.8 3.5 4.1 3.7 3.9 Δ to −0.3 −0.07 −0.07 −0.12 placebo p value0.1466 0.7306 0.7114 0.5475

FIG. 9 b : Change from Baseline in UHDRS TMS Finger Taps: Week 26patients with baseline total functional capacity (BL TFC)≥9 and CAGRepeats>44. The table below provides the P-Values corresponding to FIG.9 b . The table below and FIG. 9 b show statistically significantimprovement in the UHDRS TMS finger taps in 45 mg bid and 112.5 mg bidpridopidine treated patients having BL TFC greater than or equal to 9and greater than 44 CAG repeats in their htt gene, at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 13 15 19 22 11Baseline 2.6 2.7 3.3 3 3.6 Δ to −0.86 −0.34 −0.52 −1.07 placebo p value0.0499 0.4255 0.1972 0.0424

FIG. 9 c : Change from baseline in UHDRS TMS Finger Taps: Week 26patients with BL TFC≥9, CAG Repeats<44 and patients who represent threeleast severe TMS quarters (BL TMS 1st 3 Qs). The table below providesthe P-Values corresponding to FIG. 9 c . The table below and FIG. 9 cshow statistically significant improvement in the UHDRS TMS finger tapsin 45 mg bid and 112.5 mg bid pridopidine treated patients having BL TFCgreater than or equal to 9 and less than 44 CAG repeats in their httgene, at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 13 15 19 21 10Baseline 2.6 2.7 3.3 3 3.5 Δ to −0.87 −0.36 −0.54 −1.05 placebo p value0.05 0.41 0.1888 0.0537

FIG. 9 d : Change from baseline in UHDRS TMS Finger Taps: Patients whohave completed 52 weeks of treatment: UHDRS TMS Finger Tap score at week26. The table below provides the P-Values corresponding to FIG. 9 d .The table below and FIG. 9 d show statistically significant improvementin the UHDRS TMS finger taps in 45 mg bid pridopidine treated patientswho completed 52 weeks, at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 52 43 44 53 44Baseline 3.8 3.2 4 3.5 3.8 Δ to −0.59 −0.13 −0.01 −0.21 placebo p value0.0182 0.5881 0.9554 0.3833

FIG. 9 e : Change from baseline in UHDRS TMS Finger Taps: Patients whohave completed 52 weeks of treatment: UHDRS TMS Finger Tap score at week52. The table below provides the P-Values corresponding to FIG. 9 e .The table below and FIG. 9 e show no significant improvement in theUHDRS TMS finger taps in ALL pridopidine treated patients, at 52 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 52 43 44 53 44Baseline 3.8 3.2 4 3.5 3.8 Δ to −0.31 0.13 0.08 0.1 placebo p value0.2091 0.6027 0.7179 0.6835

FIG. 9 f : Change from baseline in UHDRS TMS FingerTapping+Pronate-Supinate Hands: Patients who have completed 52 weeks oftreatment—score at week 26. The table below provides the P-Valuescorresponding to FIG. 9 f . The table below and FIG. 9 f showstatistically significant improvement in the UHDRS TMS finger taps andPronate-Supinate Hands in 45 mg bid pridopidine treated patients whocompleted 52 weeks, at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 52 43 44 53 44Baseline 7.1 6.1 7 6.5 7 Δ to −0.79 0.02 0.02 −0.23 placebo p value0.0294 0.9443 0.9412 0.5268

FIG. 9 g : Change from baseline in UHDRS TMS FingerTapping+Pronate-Supinate Hands: Patients who have completed 52 weeks oftreatment—score at week 52. The table below provides the P-Valuescorresponding to FIG. 9 g . The table below and FIG. 9 g show nosignificant improvement in the UHDRS TMS finger taps andPronate-Supinate Hands in pridopidine treated patients at 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 52 43 44 53 44Baseline 7.1 6.1 7 6.5 7 Δ to −0.37 0.68 0.48 0.28 placebo p value0.3801 0.1066 0.2337 0.4978

FIG. 9 h : Change from baseline in UHDRS TMS Gait and Balance: Gait andbalance scores at week 26 for patients with BL TFC≥7. The table belowprovides the P-Values corresponding to FIG. 9 h . The table below andFIG. 9 h show statistically significant improvement in the UHDRS TMSgait and balances in 90 mg bid pridopidine treated HD1 and HD2 patientsat 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 62 59 54 56 58Baseline 3.2 3.7 3.4 3.5 3.1 Δ to −0.48 −0.37 −0.62 −0.49 placebo pvalue 0.0563 0.1442 0.013 0.0518

FIG. 9 i : Change from baseline in UHDRS TMS Gait and Balance: Gait andbalance scores at week 52 for patients with BL TFC≥7. The table belowprovides the P-Values corresponding to FIG. 9 i . The table below andFIG. 9 i show no significant improvement in the UHDRS TMS gait andbalances in pridopidine treated HD1 and HD2 patients at 52 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 62 59 54 56 58Baseline 3.2 3.7 3.4 3.5 3.1 Δ to −0.41 −0.43 −0.28 −0.09 placebo pvalue 0.1811 0.1691 0.365 0.7719

FIGS. 9 j-9 m provide bar graphs of changes in UHDRS TMS Dystonia scoresin 26 and 52 week patient groups.

FIG. 9 j : Change from baseline in UHDRS TMS Dystonia ALL: UHDRS TMSDystonia scores at week 26 in all patients. The table below provides theP-Values corresponding to FIG. 9 j . No significant improvement isobserved.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 4.1 3.6 4.1 4.9 4.5 Δ to −0.06 −0.34 −0.33 −0.29 placebo pvalue 0.8711 0.3778 0.3845 0.4507

FIG. 9 k : Change from baseline in UHDRS TMS Dystonia: UHDRS TMSDystonia scores for patients with BL TFC≥9 AND CAG Repeats<44 at week26. The table below provides the P-Values corresponding to FIG. 9 k .Patients with baseline TFC greater than or equal to 9, showstatistically significant improvement in the UHDRS TMS Dystonia score at45 mg bid-90 mg bid pridopidine for 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 13 15 19 22 11Baseline 3.8 1.7 2.8 3.4 1.9 Δ to −1.54 −1.58 −1.72 −1.4 placebo p value0.0313 0.0191 0.0078 0.0847

FIG. 9 l : Change from baseline in UHDRS TMS Dystonia: UHDRS TMSDystonia scores for patients with CAG Repeats<44 AND BL TMS 1st 3 Qs atweek 26. The table below provides the P-Values corresponding to FIG. 9 l. Patients with baseline TMS who represent three least severe TMSquarters and less than 44 CAG repeats in their htt gene, showstatistically significant improvement in the UHDRS TMS Dystonia score at45 mg bid-90 mg bid pridopidine for 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 29 29 32 37 22Baseline 3 2.6 2.6 2.9 2.6 Δ to −1.04 −1.15 −1 −0.62 placebo p value0.0437 0.0235 0.0399 0.2655

FIG. 9 m : Change from baseline in UHDRS TMS Dystonia: UHDRS TMSDystonia scores for patients with BL TFC≥9 and CAG Repeats<44 and BL TMS1st 3 Qs at week 26. The table below provides the P-Values correspondingto FIG. 9 m . Patients with baseline TFC greater than or equal to 9,baseline TMS representing three least severe TMS quarters and less than44 CAG repeats in their htt gene, show statistically significantimprovement in the UHDRS TMS Dystonia score at 45 mg bid 67.5 mg bid and90 mg bid pridopidine for 26 weeks.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 13 15 19 21 10Baseline 3.8 1.7 2.8 3.1 2.1 Δ to −1.53 −1.6 −1.64 −1.29 placebo p value0.0349 0.02 0.0132 0.1276

FIGS. 10 a and 10 b : General information regarding Finger tapping(Q-motor tap measurements). FIG. 10 a shows a drawing of subject's armwith tapper. FIG. 10 b shows normal and aberrant tapping measurements.

FIGS. 11 a and 11 b : Q-motor tap measurements: A well-validatedobjective measure. (Bechtel 2010)

FIG. 12 : Q-Motor Tap-Speed-Frequency. 90 mg pridopidine administeredbid demonstrated consistent improvement from baseline. The data for 90mg pridopidine bid is shown by the top line in this graph and the datafor the placebo is shown by the bottom line in this graph. Difference inp-value of 90 mg pridopidine bid from placebo was 0.0259 at week 4,0.0365 at week 12, and 0.0056 at week 26. Increase in tap speedindicates improvement. The unit of measurement of the Y-axis isFrequency (Hz).

FIGS. 13 a and 13 b : Q-Motor Tap Speed Inter Onset interval (IOI). 90mg pridopidine administered bid demonstrated consistent and significantimprovement from baseline for 90 mg bid. The data for 90 mg pridopidinebid is shown by the bottom line in this graph and the data for theplacebo is shown by the top line in this graph. Difference in p-value of90 mg pridopidine bid from placebo was 0.0342 at week 4, 0.0368 at week12, and 0.0162 at week 26. Decrease in inter tap interval indicatesimprovement. The unit of measurement of the Y-axis in FIG. 13 a isFrequency (Hz). FIG. 13 b shows change from baseline inTap-Speed-Inter-Onset-interval-MN-Hand-L (sec) over time (weeks) forfull analysis set.

FIG. 13 c : Improvement in objective pharmacodynamic measures of motorcontrol: change from baseline in Q-Motor:Tap-Speed-Inter-Onset-interval-MN-Hand (sec), Week 52 FAS. The tablebelow provides data and the P-Values corresponding to FIG. 13 c . Atrend towards improvement was noted in 45 mg bid treated patients.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 0.4065 0.4154 0.4608 0.4029 0.4366 Δ to −0.0402 0.0152 −0.0064−0.017 placebo p value 0.1956 0.6063 0.8258 0.5689

FIG. 13 d : Improvement in objective pharmacodynamic measures of motorcontrol: change from baseline in Q-Motor:Tap-Speed-Inter-Onset-interval-MN-Hand (sec), Week 52 in pridopidinetreated HD1 and HD2 patients. The table below provides the data andP-Values corresponding to FIG. 13 d . A trend towards improvement wasnoted in all treatment arms.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 62 59 54 56 58Baseline 0.3725 0.3605 0.3983 0.3789 0.4056 Δ to −0.0351 −0.0464 −0.0291−0.022 placebo p value 0.1347 0.0449 0.2039 0.3509

FIG. 13 e : Improvement in objective pharmacodynamic measures of motorcontrol, change from baseline in Q-Motor: Pro-Sup-Frequency-MN-Hand(Hz), Week 52 FAS. The table below provides the data and P-Valuescorresponding to FIG. 13 e . A trend towards improvement was noted in 45mg bid treated patients.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 81 75 79 81 81Baseline 1.6686 1.7789 1.7255 1.7505 1.7251 Wk 52 Δ 0.0599 −0.0124−0.0087 0.0127 to placebo p value 0.3122 0.8278 0.8763 0.8261

FIG. 13 f : Improvement in objective pharmacodynamic measures of motorcontrol, change from baseline in Q-Motor: Pro-Sup-Frequency-MN-Hand(Hz), Week 52 Week 52 in pridopidine treated HD1 and HD2 patients. Thetable below provides the data and P-Values corresponding to FIG. 13 f .A trend towards improvement was noted in 45 mg bid treated patients.

Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid N 62 59 54 56 58Baseline 1.77 1.8513 1.8928 1.8658 1.841 Wk 52 Δ 0.1195 0.0548 0.05750.08 to placebo p value 0.0692 0.3996 0.3709 0.229

FIG. 14 : Change from baseline in UHDRS-TMS plotted over time in HD1patients. Line with dark diamond represents placebo; line with opencircle represents 45 mg bid, line with triangle represents 67.5 mg bid,line with grey diamond represents 90 mg bid, line with square represents112.5 mg bid. 45 mg bid shows improvement in TMS score after 52 weeks. Yaxis represents change from baseline in TMS from baseline, x axisrepresents treatment time in weeks. (Adj. means±SEM)

FIG. 15 : Comparison of patients with baseline (BL) dystonia score of ≥4at 52 weeks after dosage with either placebo, 45 mg pridopidine b.i.d,67.5 mg pridopidine b.i.d., 90 mg pridopidine b.i.d., or 112.5 mgpridopidine b.i.d. Within the full analysis set, no clinicallymeaningful changes from baseline were noted for patients at Week 26 orWeek 52 in the dystonia score across the placebo and all activetreatment groups (not shown). In patients with a baseline total dystoniascore≥4 assessed at Week 52, a directional clinical improvement indystonia was noted for all treatment groups, with the greatest decreasesobserved for the 45, 67.5, and 90 mg bid treatment groups.

FIG. 16 a : Of those patients with baseline (BL) dystonia score of ≥4who completed 52 weeks of treatment with either placebo or 45 mgpridopidine b.i.d., the percentage who were categorized based on thechange in UHDRS TMS dystonia from BL to 52 weeks as responders (improvedor no change, e.g. change≥0) or non-responders (worsened, change<0).

FIG. 16 b : Of those patients with baseline (BL) dystonia score of >4who completed 52 weeks of treatment with either placebo or 45 mgpridopidine b.i.d., the percentage who were categorized based on thechange in UHDRS TMS dystonia from BL to 52 weeks as responders(improved, e.g. change≥1) or non-responders (worsened or no change<1).

Results of the Responder Analysis for dystonia items (FIGS. 16 a and 16b ) further support this trend toward improvement by showing that agreater percentage of patients were categorized as Responders within thedystonia items in the 45 mg bid treatment group compared to the placebogroup (14 patients [77.8%] and 18 patients [60.0%], respectively inFIGS. 16 a and 66.7% and 33.3%, respectively in FIG. 16 b ). A similartrend of Responders was seen in the chorea+dystonia items in the 45 mgbid treatment group compared to the placebo group (14 patients [77.8%]and 20 patients [66.7%], respectively) (not shown).

FIG. 17 : Plot of change in UHDRS Dystonia score over time for subjectspooled from MermaiHD, HART and Pride-HD studies with baseline (BL)dystonia (≥4) who received either placebo or 45 mg pridopidine b.i.d. AtWeek 26, patients taking 45 mg pridopidine b.i.d showed a statisticallysignificant improvement in the dystonia score compared to those takingplacebo. A trend toward this improvement was maintained at Week 52.

FIG. 18 : Of those PRIDE-HD patients with baseline (BL) dystonia scoreof ≥4 who completed 52 weeks of treatment with either placebo or 45 mgpridopidine b.i.d., the percentage who were categorized based on thechange in UHDRS limb dystonia from BL to 52 weeks as responders(improved, e.g. change >1) or non-responders (worsened or no change<1).

A statistically significant greater percentage of patients werecategorized as Responders for the UHDRS-Limb Dystonia item in thepridopidine 45 mg bid treatment group compared to the placebo group(77.2% and 36.7%, respectively).

FIGS. 19A and 19B present levels of dystonia over a 6 h period andcumulated in either 1 h epochs (FIG. 19A) or cumulated across the 0-2 hperiod of peak-effect (FIG. 19B). Data are median (FIG. 19A) withindividual values (FIG. 19BB). N=8 for all treatment groups. */**/***represents P<0.05, P<0.01 or P<0.001 cf vehicle-treatment. 2-way RMANOVA (FIG. 19A) with Holm-Sidak's test or Friedman test with Dunn'stest (FIG. 19B).

LDh-vehicle cf. (h) Pridopidine 1 2 3 4 5 6 15 mg/kg ns ns ns ns ns ns20 mg/kg * ns ns ns ns ns 30 mg/kg ** *** * ns ns ns

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a method of treating a subject afflicted with adystonia, comprising periodically administering to the subject apharmaceutical composition comprising an amount of pridopidine effectiveto treat the subject.

This invention provides a method of treating a subject afflicted with adystonia comprising periodically administering to the subject apharmaceutical composition comprising an amount of pridopidine or itspharmaceutically acceptable salt, effective to treat the subject,wherein the dystonia is a primary dystonia, an isolated dystonia, anearly onset generalized dystonia, a secondary dystonia, a focaldystonia, a segmental dystonia, a multifocal dystonia, a hemidystonia, ageneralized dystonia, paroxysmal dystonia, Blepharospasm (BenignEssential Blepharospasm[BEB]), Cervical Dystonia (SpasmodicTorticollis[ST]), Acquired Dystonia, Oromandibular Dystonia, Embouchuredystonia, Paroxysmal Dystonia Choreoathetosis, Paroxysmal nonkinesigenicdyskinesia (PKND), Spasmodic Dysphonia (SD), Spasmodic Torticollis(Cervical Dystonia), Tardive Dystonia, writer's Cramp dystonia or anycombination thereof.

This invention further provides a method of treating a subject afflictedwith a dystonia as a symptom of a disorder comprising: Huntingtondisease, Parkinson disease, Alzheimer disease, Wilson's disease,Multiple Sclerosis, birth injury, disorders that develop in some peoplewith cancer (paraneoplastic syndromes), oxygen deprivation or carbonmonoxide poisoning, infections such as HIV, tuberculosis orencephalitis, reactions to certain medications or heavy metal poisoning,comprising periodically administering to the subject a pharmaceuticalcomposition comprising an amount of pridopidine or its pharmaceuticallyacceptable salt effective to treat the subject or a genetic dystonias.

In some embodiments, the subject is not afflicted with Huntington'sdisease.

In some embodiments, the subject is not a Huntington's disease subject.

In one embodiment, the dystonia is a primary dystonia or an isolateddystonia. In another embodiment, the dystonia is a primary generalizeddystonia. In another embodiment, the dystonia is a genetic form ofprimary dystonia. In another embodiment, the dystonia is an early onsetgeneralized dystonia.

In one embodiment, the dystonia is Torsion dystonia-1 (DYT1) dystonia.In another embodiment, the dystonia is DYT6 dystonia or DYT-KMT2B(DYT28) dystonia. In one embodiment, the DYT1 dystonia is postural typedystonia or action type dystonia.

In some embodiments, the dystonia is early onset dystonia or late onsetdystonia. In some embodiments, the dystonia manifests at any age. Insome embodiments, the dystonia is an early onset generalized dystonia(DYT1 and non-DYT1).

In some embodiments, the dystonia is an isolated or a combined dystonia.

In some embodiment, the dystonia is a secondary dystonia or a combineddystonia.

In one embodiment, the dystonia is Dopa-responsive dystonia, Myoclonusdystonia, X-linked dystonia-parkinsonism, or Rapid-onsetdystonia-parkinsonism.

In some embodiments, the dystonia is a focal dystonia, a segmentaldystonia, a multifocal dystonia, a hemidystonia or a generalizeddystonia.

In one embodiment, the dystonia is a paroxysmal dystonia. In anotherembodiment the dystonia is action-specific dystonia or a task-specificdystonia. In one embodiment, the dystonia is Musician's dystonia.

In one embodiment, the dystonia is not caused by a pathology. In someembodiments, the pathology is a stroke, a traumatic brain injury, alesion, a brain tumor, neurological tissue damage, or neurologicaltissue degeneration.

In some embodiments, the dystonia is Musician's dystonia,Dopa-responsive dystonia, Myoclonus dystonia, Paroxysmal dystonia anddyskinesia, X-linked dystonia-parkinsonisms, Rapid-onsetdystonia-parkinsonisms, Primary dystonia, Secondary dystonia (includingHuntington's dystonia), or Psychogenic dystonia.

In one embodiment, the dystonia is postural dystonia. In anotherembodiment, the dystonia is action dystonia.

In an embodiment, the subject has been confirmed to be afflicted withDYT1 or other primary genetic forms of dystonia by genetic testing. Inan embodiment, the subject has a Burke-Fahn-Marsden Dystonia RatingScale (BFMDRS) score greater than 6.

In one embodiment, the subject has a 3-base pair in-frame deletionwithin the coding region of the TOR1A (torsinA) gene located onchromosome 9q34.

In one embodiment, the subject does not suffer from cognitiveimpairment. In another embodiment, the subject suffers from a cognitiveimpairment.

In an embodiment, the amount of pridopidine is effective to reduce ormaintain a level of one or more symptoms of the dystonia in the subject.In an embodiment, the symptoms are measured by the Burke-Fahn-MarsdenDystonia Rating Scale or the Unified Dystonia Rating Scale. In anotherembodiment, the symptoms are measured by the Clinical Global Impression(CGI) scale, Patient Global Assessment score, Visual Analogue Score forpain, Patient Evaluation of Global Response, Burke-Fahn-MarsdenDisability Scale (BFMDS), or the Health Related quality of life score(EQ-5D, SF-36).

In one embodiment, the one or more symptom is dystonia.

In an embodiment, the one or more symptoms are selected from the groupconsisting of: involuntary limb movement or muscle contractions; twistedposture of the limbs or trunk; abnormal fixed posture of the limbs ortrunk; talipes equinovarus; turning in of the leg; turning in of thearm; tremor of the hand, head, trunk or arms; dragging of the leg;torticollis; writer's cramp; and dystonia of trunk and/or extremities.

In one embodiment, the amount of pridopidine is effective to provide aclinically significant improvement in dystonia symptoms. In anembodiment, the clinically significant improvement in dystonia symptomsis an at least a 20% change from baseline in the subject administeredpridopidine in comparison to a human patient not treated withpridopidine as measured by a rating scale used in clinical practice orclinical research. In an embodiment, the rating scale used in clinicalpractice or clinical research is the dystonia items of the UHDRS scaleor the Burke-Fahn-Marsden Dystonia Rating Scale. In some embodiments, aclinically significant improvement in dystonia symptoms is considered tobe at least a 20% change from baseline in a pridopidine treated patientcompared to placebo treated patient (a patient not receivingpridopidine) when measured using a rating scale used in clinicalpractice or clinical research such as, for example, the dystonia itemsof the UHDRS scale or BFMDRS. In some embodiments, a clinicallysignificant improvement is at least a 25% change from baseline, a 30%change from baseline, a 40% change from baseline or a greater than 50%change from baseline.

In an embodiment, the subject is a human patient. In another embodiment,the subject is a mammal. In one embodiment, the periodic administrationis oral.

In an embodiment, between 22.5-315 mg pridopidine is administered to thepatient per day. In another embodiment, 22.5 mg, 45 mg, 67.5 mg, 90 mg,100 mg, 112.5 mg, 125 mg, 135 mg, 150 mg, 180 mg, 200 mg, 250 mg, or 315mg pridopidine is administered to the patient per day.

In an embodiment, the amount of pridopidine is administered by a unitdose of 22.5 mg, 45 mg, 67.5 mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 135mg, 150 mg, 180 mg, 200 mg, 250 mg, or 315 mg pridopidine.

In an embodiment, the unit dose is administered once daily.

In an embodiment, the unit dose is administered more than once daily. Inanother embodiment, the unit dose is administered twice per day.

In an embodiment, the pridopidine is in the form of pridopidinehydrochloride.

The invention also provides pridopidine for use in treating a subjectafflicted with a dystonia.

The invention also provides pridopidine for the manufacture of amedicament for use in treating a subject afflicted with a dystonia.

The invention also provides a pharmaceutical composition comprising aneffective amount of pridopidine for treating a dystonia

The invention also provides a pharmaceutical composition comprisingpridopidine or for use in treating a subject suffering from a dystonia.

The invention also provides a package comprising:

-   -   a) a pharmaceutical composition comprising an amount of        pridopidine; and    -   b) instructions for use of the pharmaceutical composition to        treat a subject afflicted with a dystonia.

The invention also provides a therapeutic package for dispensing to, orfor use in dispensing to, a subject afflicted with dystonia, whichcomprises:

-   -   a) one or more unit doses, each such unit dose comprising an        amount of pridopidine thereof, wherein the amount of said        pridopidine in said unit dose is effective, upon administration        to said subject, to treat the subject, and    -   b) a finished pharmaceutical container therefor, said container        containing said unit dose or unit doses, said container further        containing or comprising labeling directing the use of said        package in the treatment of said subject.

Combinations of the above-described embodiments are also within thescope of the invention.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. For instance, all combinationsof the various elements described herein are within the scope of theinvention. Additionally, the elements recited in the packaging andpharmaceutical composition embodiments can be used in the method and useembodiments described herein.

Pharmaceutical Compositions

While the compounds for use according to the invention may beadministered in the form of the raw compound, it is preferred tointroduce the active ingredients, optionally in the form ofphysiologically acceptable salts, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In an embodiment, the invention provides pharmaceutical compositionscomprising the active compounds or pharmaceutically acceptable salts orderivatives thereof, together with one or more pharmaceuticallyacceptable carriers therefore, and, optionally, other therapeutic and/orprophylactic ingredients know and used in the art. The carrier(s) mustbe “acceptable” in the sense of being compatible with the otheringredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered byany convenient route, which suits the desired therapy. Preferred routesof administration include oral administration, in particular in tablet,in capsule, in dragé, in powder, or in liquid form, and parenteraladministration, in particular cutaneous, subcutaneous, intramuscular, orintravenous injection. The pharmaceutical composition of the inventioncan be manufactured by the skilled person by use of standard methods andconventional techniques appropriate to the desired formulation. Whendesired, compositions adapted to give sustained release of the activeingredient may be employed.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences (MackPublishing Co., Easton, PA).

Terms

As used herein, and unless stated otherwise, each of the following termsshall have the definition set forth below.

The articles “a”, “an” and “the” are non-limiting. For example, “themethod” includes the broadest definition of the meaning of the phrase,which can be more than one method.

As used herein, “effective” as in an amount effective to achieve an endmeans the quantity of a component that is sufficient to yield anindicated therapeutic response without undue adverse side effects (suchas toxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of thisdisclosure. For example, an amount effective to treat a movementdisorder. The specific effective amount varies with such factors as theparticular condition being treated, the physical condition of thepatient, the type of mammal being treated, the duration of thetreatment, the nature of concurrent therapy (if any), and the specificformulations employed and the structure of the compounds or itsderivatives

As used herein, to “treat” or “treating” encompasses, e.g., reducing asymptom, inducing inhibition, regression, or stasis of the disorderand/or disease. As used herein, “inhibition” of disease progression ordisease complication in a subject means preventing or reducing thedisease progression and/or disease complication in the subject.

“Administering to the subject” or “administering to the (human) patient”means the giving of, dispensing of, or application of medicines, drugs,or remedies to a subject/patient to relieve, cure, or reduce thesymptoms associated with a condition, e.g., a pathological condition.The administration can be periodic administration.

As used herein, “periodic administration” means repeated/recurrentadministration separated by a period of time. The period of time betweenadministrations is preferably consistent from time to time. Periodicadministration can include administration, e.g., once daily, twicedaily, three times daily, four times daily, weekly, twice weekly, threetimes weekly, four times a week and so on, etc.

“Dystonia” as referred to herein is a movement disorder characterized bysustained or intermittent muscle contractions causing abnormal, oftenrepetitive, movements, postures, or both. Dystonic movements aretypically patterned, twisting, and may be tremulous. Dystonia is ofteninitiated or worsened by voluntary action and associated with overflowmuscle activation (Albanese 2013a).

As used herein, an “amount” or “dose” of pridopidine as measured inmilligrams refers to the milligrams of pridopidine present in apreparation, regardless of the form of the preparation. A “dose of 90 mgpridopidine” means the amount of pridopidine acid in a preparation is 90mg, regardless of the form of the preparation. Thus, when in the form ofa salt, e.g. a pridopidine hydrochloride, the weight of the salt formnecessary to provide a dose of 90 mg pridopidine would be greater than90 mg due to the presence of the additional salt ion.

By any range disclosed herein, it is meant that all hundredth, tenth andinteger unit amounts within the range are specifically disclosed as partof the invention. Thus, for example, 0.01 mg to 50 mg means that 0.02,0.03 . . . 0.09; 0.1; 0.2 . . . 0.9; and 1, 2 . . . 49 mg unit amountsare included as embodiments of this invention.

As used herein, “pridopidine” means pridopidine base or apharmaceutically acceptable salt thereof, as well as derivatives, forexample deuterium-enriched version of pridopidine and salts. Examples ofdeuterium-enriched pridopidine and salts and their methods ofpreparation may be found in U.S. Application Publication Nos.2013-0197031, 2016-0166559 and 2016-0095847, the entire content of eachof which is hereby incorporated by reference. In certain embodiments,pridopidine is a pharmaceutically acceptable salt, such as the HCl saltor tartrate salt. Preferably, in any embodiments of the invention asdescribed herein, the pridopidine is in the form of its hydrochloridesalt.

“Deuterium-enriched” means that the abundance of deuterium at anyrelevant site of the compound is more than the abundance of deuteriumnaturally occurring at that site in an amount of the compound. Thenaturally occurring distribution of deuterium is about 0.0156%. Thus, ina “deuterium-enriched” compound, the abundance of deuterium at any ofits relevant sites is more than 0.0156% and can range from more than0.0156% to 100%. Deuterium-enriched compounds may be obtained byexchanging hydrogen with deuterium or synthesizing the compound withdeuterium-enriched starting materials.

Pharmaceutically Acceptable Salts

The active compounds for use according to the invention may be providedin any form suitable for the intended administration. Suitable formsinclude pharmaceutically (i.e. physiologically) acceptable salts, andpre- or prodrug forms of the compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride, the hydrobromide, the L-tartrate, the nitrate, theperchlorate, the phosphate, the sulphate, the formate, the acetate, theaconate, the ascorbate, the benzenesulphonate, the benzoate, thecinnamate, the citrate, the embonate, the enantate, the fumarate, theglutamate, the glycolate, the lactate, the maleate, the malonate, themandelate, the methanesulphonate, the naphthalene-2-sulphonate, thephthalate, the salicylate, the sorbate, the stearate, the succinate, thetartrate, the toluene-p-sulphonate, and the like. Such salts may beformed by procedures well known and described in the art.

Dystonia Rating Scales

Albanese et al, (2013b) describes the results of a task force convenedto critique existing dystonia rating scales and place them in clinicaland clinimetric context.

Listing of Abbreviations

The following abbreviations are used throughout this application:

ALT: alanine aminotransferase; ADL: Activities of Daily Living; AR:Autoregressive; AUC: area under the concentration-time curve; bid orb.i.d.: twice daily; BL=Baseline; CAB: cognitive assessment battery;CGI-C: Clinical Global Impression of Change; CGI-S: Clinical GlobalImpression of Severity; CI: confidence interval; CIBIC-Plus: Clinician'sInterview-based Impression of Change plus Caregiver Input; CIBIS:Clinician's Interview-based Impression of Severity; CIOMS: Council forInternational Organizations of Medical Sciences; Cmax: maximum observedplasma drug concentration; CNS: central nervous system; CRF: case reportform; CRO: contract research organization; CS: Compound Symmetry;C-SSRS: Columbia-Suicide Severity Rating Scale; CYP: cytochrome P450;DSM-IV TR: Diagnostic and Statistical Manual—Fourth Edition TextRevision; EM: extensive metabolizers; EU: European Union; FA: FunctionalAssessment; FAS: full analysis set; Freq: tapping frequency; GCP: GoodClinical Practice; GFV-C: grip force variability in the static phase;GGT: gamma-glutamyl transpeptidase; HART: Huntington's disease ACR16Randomized Trial; HCG: human chorionic gonadotropin; HD: Huntington'sdisease; HD-QoL=Huntington's disease Quality of Life; HVLT-R: HAD-CABHopkins Verbal Learning Test-Revised; ICH:

International Conference on Harmonisation; IEC: Independent EthicsCommittee; IOI: inter onset interval; IPI: inter peak interval; IRB:Institutional Review Board; IRT: interactive response technology; IS:Independence Score; ITI: inter tap interval; ITT: intent-to-treat; LSO:local safety officer; MAD: multiple ascending dose; MedDRA: MedicalDictionary for Regulatory Activities; MermaiHD: Multinational EuropeanMulticentre ACR16 study in Huntington's Disease; ML: Maximum-Likelihood;mMS: Modified Motor Score; MoCA: Montreal cognitive assessment; MS:Multiple sclerosis; MTD: maximum tolerated dose; NMDA:N-methyl-D-aspartate; NOAEL: no observed adverse effect level; PBA-s:Problem Behaviors Assessment-Short form; PD: pharmacodynamic(s); PDS:Physical disability scale; PK: pharmacokinetic(s); PM: poor metabolizer;PPT: physical performance test; Qd: once daily; Q-Motor: Quantitativemotor; QoL: Quality of life; QTcF: Fridericia-corrected QT interval;RBC: red blood cell; REML: Restricted Maximum-Likelihood; SAE: seriousadverse event; SD: standard deviation; SDMT: symbol digit modalitiestest; SOC: system organ class; SOP: standard operating procedure; SUSAR:suspected unexpected serious adverse reaction; t½: half life;TC=telephone call; TD: tap duration; TF: tapping force; TFC: TotalFunctional Capacity; TMS: Total Motor Score; TMS InvoluntaryMovements=TMS for performance of Domestic Chores and Dystonia scorescombined. TUG: timed up and go; UHDRS: Unified Huntington's DiseaseRating Scale; ULN: upper limit of the normal range; US: United States;WBC: white blood cell; WHO: World Health Organization; WHO: Drug WorldHealth Organization (WHO) drug dictionary; ΔHR: change from baseline inheart rate; ΔQTcF: change from baseline in QTcF; ΔΔHR: placebo-correctedchange from baseline in heart rate; Placebo-ControlledStudy—Huntington's Disease; ΔΔQTcF: placebo-corrected change frombaseline in QTcF, wk: week; EQ5D-5L European Quality of Life-5Dimensions (5 levels).

Clinical Studies

Sixteen (16) clinical studies have been completed with pridopidine,including 8 studies in healthy subjects (of which 1 study also includedpatients with schizophrenia), 1 study in patients with Parkinson'sdisease, 2 studies in patients with schizophrenia (including the studymentioned above), and 6 studies in patients with HD (including 1open-label extension study). In addition, a compassionate use programfor pridopidine in patients with HD is ongoing in Europe, and anopen-label, long term safety study is ongoing in the United States (US)and Canada. An overview of these studies are presented in InternationalPublication No. WO 2014/205229, the content of which is herebyincorporated by reference.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXAMPLES Example 1 A Phase II, Dose-finding, Randomized, Parallel-Group,Double-Blind, Placebo-Controlled Study, Evaluating the Safety andEfficacy of Pridopidine 45 mg, 67.5 mg, 90 mg, and 112.5 mg Twice-Dailyversus Placebo for Symptomatic Treatment in Patients with Huntington'sDisease (“PRIDE-HD”)

The PRIDE-HD study assessed the efficacy of pridopidine 45 mg to 112.5mg twice daily (bid) on motor impairment in patients with HD over atleast 52 weeks of treatment using the Unified Huntington's DiseaseRating Scale (UHDRS) Total Motor Score (TMS). The study also assessedthe effect of at least 52 weeks of treatment with pridopidine 45 mg bidto 112.5 mg bid on the Modified Physical Performance Test (mPPT). Thestudy also assessed the effect of at least 52 weeks of treatment withpridopidine 45 mg bid to 112.5 mg bid on UHDRS measures for totalfunction capacity (TFC) and cognitive assessment battery (CAB). Thestudy also compared data from all patients to those obtained in HDsubpopulations. The study also (i) evaluated the safety and tolerabilityof a range of pridopidine doses in patients with HD during at least 52weeks of treatment, (ii) explored the pharmacokinetics (PK) ofpridopidine in the study population and (iii) investigated therelationship between exposure to pridopidine and outcome measures (e.g.,clinical efficacy and toxicity parameters).

Study Design

General Design and Study Schema

This was a randomized, parallel-group, double blind, placebo controlledstudy that compared the efficacy and safety of pridopidine 45 mg, 67.5mg, 90 mg, and 112.5 mg bid versus placebo in the treatment of motorimpairment in HD.

The administration of pridopidine to patients is summarized in Table 2.The study procedures and assessments are summarized in Table 3. Adetailed clinical procedure, including screening procedures and otherprocedures, is listed as Example 3 in U.S. Patent ApplicationPublication No. US 2014/0378508 and International Publication No. WO2014/205229, the content of which are hereby incorporated by reference.

Primary and Secondary Variables and Endpoints

The primary efficacy variable and endpoint for this study was changefrom baseline in the UHDRS TMS (defined as the sum of all UHDRS motordomains ratings) at Week 26 or Week 52. The primary measure of motorimpairment is the UHDRS motor assessment section, which was administeredby a trained examiner. The first part of the motor assessment consistedof five TMS subscores, provided below. The sum total of all the 31 itemsis referred to as the Total Motor Score (TMS). The secondary efficacyvariable and endpoint was change from baseline in the mPPT at Week 26 orWeek 52. The TMS scale includes measurement of dystonia.

Other Efficacy Variables and Endpoints

Other efficacy variables and endpoints for this study are as follows:

-   -   Global Functional Scales:    -   CIBIC-Plus global score as compared to baseline    -   Change from baseline in the PDS score    -   Change from baseline in UHDRS FA    -   CGIC as compared to baseline    -   Change from baseline in UHDRS TFC    -   Change from baseline in UHDRS IS    -   Global/Functional Scales:    -   Change from baseline in HD QoL    -   Change from baseline in Walk-12 scale    -   TMS Subscores:    -   Change from baseline in hand movement score (defined as the sum        of UHDRS domains finger taps, pronate-supinate hands and luria        [fist-hand-palm test])    -   Change from baseline in Gait and balance score (defined as the        sum of UHDRS domains gait, tandem walking and retropulsion pull        test)    -   Change from baseline in UHDRS mMS (defined as the sum of UHDRS        domains dysarthria, tongue protrusion, finger taps,        pronate-supinate hands, luria, rigidity, bradykinesia, gait,        tandem walking, retropulsion pull test)    -   Change from baseline in UHDRS Chorea    -   Change from baseline in UHDRS Dystonia    -   Responders, defined as patients with UHDRS TMS change from        baseline <0    -   Other Motor Assessments:    -   Change from baseline in Q Motor measurements including        digitomotography (speeded index finger tapping),        dysdiadochomotography (pronation/supination hand tapping),        manumotography and choreomotography (grip force and chorea        analysis) and pedomotography (speeded foot tapping)    -   Change from baseline in the TUG test    -   Cognitive/Psychiatric Assessments:    -   Change from baseline in HD-CAB brief: SDMT, Emotion Recognition,        Trail Making Test, HVLT-R, Paced Tapping at 3 Hz, OTS.    -   Change from baseline in PBA-s        Safety Variables and Endpoints        Safety variables and endpoints include the following:    -   AEs throughout the study    -   Changes from baseline in QTcF and other ECG parameters        throughout the study    -   Clinical safety laboratory (clinical chemistry, hematology, and        urinalysis) throughout study    -   Changes from baseline C-SSRS throughout the study    -   Vital signs throughout the study        Tolerability Variables and Endpoints        Tolerability variables and endpoints include the following:    -   the number (%) of patients who failed to complete the study    -   the number (%) of patients who failed to complete the study due        to AEs        Pharmacokinetic Variables and Endpoints

The primary PK measure was determination of plasma concentration ofpridopidine. Concentrations were also incorporated into a pridopidinepopulation PK model and individual exposure for the study patients (Cmaxand AUC) was calculated.

Study Drugs and Dosage

Pridopidine (as pridopidine hydrochloride) was provided as a white hardgelatin capsule, size 2 containing 45 mg pridopidine and a white hardgelatin capsule, size 4 containing 22.5 mg pridopidine. Placebo waspresented as white hard gelatin capsules matching the 22.5 mg or 45 mgpridopidine capsules but containing no active ingredient, only theexcipients (silicified microcrystalline cellulose and magnesiumstearate).

TABLE 2 Dose Administration (Capsules were Administered Twice Daily toGive the Total Daily Dose) Titration Period Full Dose Period TreatmentWeek 1 Week 2 Week 3 Week 4^(a) Weeks 4^(b)to 52 Pridopidine 1 × 22.5 mgPridopidine 1 × 22.5 mg Pridopidine 1 × 22.5 mg Pridopidine 1 × 22.5 mgPridopidine 1 × 45 mg Pridopidine 45 mg bid 1 × 22.5 mg Placebo 1 × 22.5mg Placebo 1 × 22.5 mg Placebo 1 × 22.5 mg Placebo 1 × 22.5 mg Placebo 1× 45 mg Placebo 1 × 45 mg Placebo 1 × 45 mg Placebo 1 × 45 mg Placebo 1× 45 mg Placebo (TDD = 45 mg) (TDD = 45 mg) (TDD = 45 mg) (TDD = 45 mg)(TDD = 90 mg) Pridopidine 1 × 22.5 mg Pridopidine 1 × 22.5 mgPridopidine 1 × 45 mg Pridopidine 1 × 45 mg Pridopidine 1 × 22.5 mgPridopidine 67.5 mg bid 1 × 22.5 mg Placebo 1 × 22.5 mg Placebo 2 × 22.5mg Placebo 2 × 22.5 mg Placebo 1 × 45 mg Pridopidine 1 × 45 mg Placebo 1× 45 mg Placebo (TDD = 90 mg) (TDD = 90 mg) 1 × 45 mg Placebo (TDD = 45mg) (TDD = 45 mg) (TDD = 135 mg) Pridopidine 1 × 22.5 mg Pridopidine 1 ×45 mg Pridopidine 1 × 45 mg Pridopidine 1 × 45 mg Pridopidine 2 × 45 mgPridopidine 90 mg bid 1 × 22.5 mg Placebo 2 × 22.5 mg Placebo 1 × 22.5mg Pridopidine 1 × 22.5 mg Pridopidine 1 × 22.5 mg Placebo 1 × 45 mgPlacebo (TDD = 90 mg) 1 × 22.5 mg Placebo 1 × 22.5 mg Placebo (TDD = 180mg) (TDD = 45 mg) (TDD = 135 mg) (TDD = 135 mg) Pridopidine 1 × 22.5 mgPridopidine 1 × 45 mg Pridopidine 1 × 45 mg Pridopidine 1 × 45 mgPridopidine 1 × 22.5 mg Pridopidine 112.5 mg bid 1 × 22.5 mg Placebo 2 ×22.5 mg Placebo 1 × 22.5 mg Pridopidine 2 × 22.5 mg Pridopidine 2 × 45mg Pridopidine 1 × 45 mg Placebo (TDD = 90 mg) 1 × 22.5 mg Placebo (TDD= 180 mg) (TDD = 225 mg) (TDD = 45 mg) (TDD = 135 mg) Placebo 2 × 22.5mg Placebo 2 × 22.5 mg Placebo 2 × 22.5 mg Placebo 2 × 22.5 mg Placebo 1× 22.5 mg Placebo 1 × 45 mg Placebo 1 × 45 mg Placebo 1 × 45 mg Placebo1 × 45 mg Placebo 2 × 45 mg Placebo TDD = total daily dose;^(a)Excluding Day 28; ^(b)Day 28 only

TABLE 3 Study Procedures and Assessments Screening Titration Period FullDose Treatment Follow Up Procedures and Assessments First 26-Week StudyPeriod Second 26-week Study Period Visit V0^(a) V1 TC V2 TC V3 TC V4^(a)V5^(a) V6^(a) V7^(a) V8^(a) V9^(a) TC V10^(a) TC TC TC V11^(a) V12^(a)Maximum 280-308 322-357 Day 12 weeks 0 6 ± 3 14 ± 3 20 ± 3 28 ± 3 35 ± 342 ± 5 56 ± 5 84 ± 7 112 ± 7 140 ± 7 182 ± 7 224 ± 10 273 ± 7 ± 10 315 ±10 ± 10 364 ± 7 378 ± 7 week week week week week week week week weekweek week week week week week week week week Procedures and assessmentsScreening BL 1 2 3 4 5 6 8 12 16 20 26 32 39 40-44 45 46-51 52 54Abbreviated PBA-s X^(m) X^(m) X^(m) CIBIS X CIBIC-Plus X X X X PDS X X XX X CGI-S X CGI-C X X X X HD•QoL X X X EQ5D•5L X X X Walk-12 X X X X XQ•Motor assessments^(b) X X X X X X X TUG Test X X X X Cognitiveassessment battery^(b) X X X X X Blood samples for drug X^(f) X^(p)X^(q) X^(q) X^(p) X^(q) X^(p) X X^(f) X^(g) concentration (trough)Adverse event inquiry X X X X X X X X X X X X X X X X X X X Concomitantmedication X X X X X X X X X X X X X X X X X X X inquiry Benzodiazepinesand X X X X X antidepressants inquiry^(†) Alcohol/Illicit drug use X X XX X inquiry Review of tolerability to X X X study drug prior ro doseescalation (if applicable) Dispense/collect study drug X X X X X X X X XX^(g) Review study compliance & X X X X X X X X X X X^(v) X^(v) X^(v) Xadherence Study drug administration^(w%)

Table 3 Legend

a The procedures and assessments for these visits (V0 and V4-12) may beperformed over several days, as long as they are completed within thedefined visit window.

b. Inclusion/exclusion criteria should be met at screening and reviewedon Day 0 before the patient is randomized.

c Electrolytes only.

d Serum pregnancy test at screening (with urine test if required forconfirmation); urine pregnancy test at subsequent time points. Anindeterminate reading for the serum pregnancy test should be checkedtwice (urine test) and the patient referred to a gynecologist ifrequired.

e At screening, a single ECG was performed. When evidence of a prolongedQTcF interval at screening (defined as a QTcF interval of >450 msec) wasdetected then the ECG was repeated twice, and the mean of the 3screening measurements was used to determine whether or not the patientis suitable for inclusion in the study.

f At the Baseline visit, the predose QTcF was determined by the averageof 3 ECGs (within 10 to 20 minutes of one another), each in triplicate(in total 9 recordings).

A postdose ECG was performed in triplicate 1 to 2 hours after firstdosing. PK samples were collected prior to and 1 to 2 hours after firstdose administration at the site.

When concomitant to ECG, PK samples are collected after the ECGrecording.

g One ECG performed in triplicate prior and 1 to 2 hours post afternoondose.

h ECG is optional on Week 8, unless required by local regulations. It isto be performed at the investigator's discretion where there areclinical circumstances that justify an additional ECG, eg, patients witha previous episode of hypokalemia without QT prolongation.

i On Week 52, a triplicate ECG and PK sample were collected before thelast study (morning) dose.

j ECG is optional at the follow up visit, but should be performed forall patients with a previously observed cardiac concern and/or QTcchange from baseline.

k Including CAG analysis, cytochrome P450 2D6 status, genetic long QTsyndrome (assessed only in patients experiencing QT prolongationfollowing study drug administration leading to study discontinuation),or any other genetic analyses related to pridopidine response orHuntington's disease.

l Evaluated in priority.

m The safety telephone calls included an abbreviated PBA-s (a subset ofPBA questions on depressed mood, suicidal ideation, anxiety,irritability, loss of motivation and obsessive compulsive behaviors).

n Included digitomotography (speeded index finger tapping),dysdiadochomotography (pronation/supination hand tapping),manumotography and choreomotography (grip force and chorea analysis) andpedomotography (speeded foot tapping).

o Included SDMT, Emotion recognition, Trail Making Test A+B, HVLT-R;Paced Tapping Test and OTS.

p On Weeks 2, 12 and 20, PK samples were collected 1 to 2 hours postafternoon dose. When concomitant to ECG, PK samples were collected afterthe ECG recording.

q On Weeks 4, 6 and 16, PK samples were collected prior and 1 to 2 hourspost afternoon dose. When concomitant to ECG, PK samples were collectedafter the ECG recording.

r On the last study day (week 52), the study drug administration willtake place on site, after the pre-dose PK sample is obtained.

s At the follow up visit, 1 PK sample were collected. In case of SAE, anadditional PK sampling should be aimed to be collected at the closesttime to SAE. When concomitant to ECG, PK samples were collected afterthe ECG recording.

t This information were collected as part of concomitant medicationinquiry.

u Collection only.

v Study adherence is reviewed during the TCs.

w Every patient received 3 capsules twice daily (bid), ie, 3 capsules inthe morning and 3 capsules in the afternoon (7 to 10 hours after themorning dose), during the whole study period. Study drug was notadministered at Early Termination visit. At on-site visits, theafternoon dose were taken at the site.

x Patients, who for safety or tolerability reasons have to stop studydrug medication, were asked to continue in the study and follow thevisit schedule as outlined without taking study drug.

Primary Efficacy Variable and Endpoint

The UHDRS comprises a broad assessment of features associated with HD(Huntington Study Group 1996). It is a research tool which has beendeveloped to provide a uniform assessment of the clinical features andcourse of HD. The TMS component of UHDRS comprises 31 assessments fromthe 15 items of the UHDRS, with each assessment rated on a 5-point scalefrom 0 (normal) to 4 (maximally abnormal).

Secondary Efficacy Variable and Endpoint

The secondary efficacy variable and endpoint, the Modified PhysicalPerformance Test (mPPT), quantifies the patient's performance inphysical tasks (Brown 2000). It is a standardized 9-item test thatmeasures the patient's performance on functional tasks. Assistivedevices are permitted for the tasks that require a standing position(items 6 to 9). Both the speed and accuracy at which the patientscomplete the items were taken into account during scoring. The maximumscore of the test is 36, with higher scores indicating betterperformance.

Other Efficacy Variables and Endpoints

Clinician Interview Based Impression of Change plus Caregiver Input

The CIBIC-Plus (version ADCS-CGIC) was developed, validated, and iscommonly used in studies of anti-dementia drugs in Alzheimer's disease(Joffres 2000). An independent rater evaluated the patient's overalldisease severity prior to the initiation of pridopidine or placebo. Thisassessment, known as the CIBIS, rates the patient on a 7-point Likertscale from extremely severe HD to no symptoms of HD.

Physical Disability Scale

The PDS was used during the study as a measure of disability. Patientswere scored on a scale from 10 (“Fixed posture requiring totalcare—gastrotomy, catheterization”) to 100 (“Normal; no disease evident”)(Myers 1991).

UHDRS Functional Assessments or UHDRS Total Functional Assessment

The FA scale of the UHDRS assessed functionality in 25 tasks of dailyliving (e.g., “Could patient engage in gainful employment in his/heraccustomed work?”). Each question was answered with ‘yes’ or ‘no’.

Clinical Global Impression of Severity and Change

CGI-S was assessed at baseline and CGI-C was used at all subsequent timepoints to assess changes from baseline. The CGI-S scale was initiallydesigned to assess treatment response in patients with mental disorders(Guy 1976) but is now used widely in a range of illnesses.

UHDRS Total Functional Capacity

The TFC scale of the UHDRS is a standardized scale used to assess 5functional domains associated with disability shown below (occupation,finances, domestic chores (e.g. laundry, washing dishes), activities ofdaily living, and care level). Total functional capacity score has arange of 0-13 and is a well-established endpoint for trials aimingdisease progression. The Total functional capacity score has beendeveloped and deployed by the Huntington Study Group (HSG, 1996) inmultiple trials over 2 decades and is accepted by regulators.

Functional Capacity:

Occupation: 0=unable, 1=marginal work only, 2=reduced capacity for usualjob, 3=normal.

Finances: 0=unable, 1=major assistance, 2=slight assistance, 3=normal.

Domestic Chores: 0=unable, 1=impaired, 2=normal.

ADL: 0=total care, 1=gross tasks only, 2=minimal impairment, 3=normal.

Care level: 0=fill time skill nursing, 1=home or chronic care, 2=home.

UHDRS Independence Scale

The independence scale of the UHDRS is a rating scale where thepatient's degree of independence was given in percentage, from 10% (tubefed, total bed care) to 100% (no special care needed).

Global/Functional Scales

Huntington's Disease Quality of Life

The HD-QoL is a standardized instrument for measuring health-relatedquality of life. (Hocaoglu 2012). It is a validated disease-specificmeasure designed for HD, and can provide a summary score of overallhealth-related quality of life, as well as scores on several discretescales.

Total Motor Score Subscores

UHDRS Hand Movement Score or UHDRS TMS Hand Movement Score

The hand movement score is defined as the sum of UHDRS domains fingertaps, pronate-supinate hands and luria (fist-hand-palm test).

UHDRS Gait and Balance Score or UHDRS TMS Gait and Balance Score

The gait and balance score is defined as the sum of UHDRS domains gait,tandem walking and retropulsion pull test.

UHDRS Modified Motor Scale or UHDRS TMS Modified Motor Scale

The UHDRS-mMS is defined as the sum of following domains from UHDRS-TMS:dysarthria, tongue protrusion, finger taps, pronate-supinate hands,luria, rigidity, bradykinesia, gait, tandem walking, and retropulsionpull test.

UHDRS Chorea or UHDRS TMS Chorea

In the UHDRS, maximal chorea was scored from 0 (absent) to 4(marked/prolonged) on each of the following items: face, mouth, trunk,right upper extremity, left upper extremity, right lower extremity, andleft lower extremity. Maximal chorea is the sum of all scores.

UHDRS Dystonia or UHDRS TMS Dystonia

In the UHDRS, maximal dystonia was scored from 0 (absent) to 4(marked/prolonged) on each of the following items: trunk, right upperextremity, left upper extremity, right lower extremity, and left lowerextremity. Maximal dystonia is the sum of all scores.

TMS Proportion of Responders

The percentage of responders, defined as patients with UHDRS-TMS changefrom baseline≤0 at Week 26.

Other Motor Assessments

Multiple Sclerosis Walking Scale

The Multiple Sclerosis Walking Scale (MSWS-12) was adapted to become ageneric measure of walking and mobility and renamed the Walk-12.

European Quality of Life-3 Dimensions (3 Levels)

The EQSD 3 level version (EQSD-3L) was introduced in 1990 (EuroQol Group1990). It essentially consists of the EQSD descriptive system and the EQvisual analogue scale (EQ VAS). The EQSD-3L descriptive system comprisesthe following 5 dimensions: mobility, self-care, usual activities,pain/discomfort and anxiety/depression.

Quantitative Motor (Q-motor) Assessments

Motor deficits can be objectively assessed using different Q-Motorassessments. All Q-Motor assessments are based on the application ofprecalibrated and temperature controlled force transducers and3-dimensional position sensors with very high sensitivity andtest-retest reliability across sessions and sites in a multicenterclinical study. Q-Motor measures thus aim to reduce the limitedsensitivity of categorical clinical rating scales, the intra- andinter-rater variability, and placebo effects observed in scales such asUHDRS-TMS. In addition, Q-Motor assessments allow for the objectivemonitoring of unintended motor side-effects in clinical studies. Thus,Q-Motor is an objective, reliable, and sensitive measure of motorfunction that is free of rater bias and limits placebo effect influence.FIG. 10 shows the Q-motor tap measurements for a normal patient, apatient with mild defects and a patient with severe defects. InTrack-HD, the largest natural history study of pre-manifest and earlystage HD Q-motor tapping deficits correlated with clinical scores aswell as regional brain atrophy (FIGS. 11 a, 11 b , 12 and Bechtel 2010).

Digitomotography (Speeded Index Finger Tapping)

The patient places their hand on a hand rest with their index fingerpositioned above a force-transducer. Recordings start after practiceruns. The patient is instructed to finger tap as fast as possiblebetween 2 auditory cues. The beginning of a tap is defined as a rise ofthe force by 0.05 N above maximal baseline level. The tap ends when itdrops to 0.05 N before the maximal baseline level is reached again. Theduration and variability of tap durations (TD), inter onset intervals(IOI), inter peak intervals (IPI), and inter tap intervals (ITI) are theexploratory outcome measures for speeded tapping. In addition,variability of peak tapping forces (TF) is calculated as coefficient ofvariation, and the tapping frequency (Freq), i.e., the number of tapsbetween the onsets of the first and the last tap divided by the time inbetween, is determined. Five trials of 10 seconds duration are performedwith each hand.

Dysdiadochomotography (Pronation/Supination Hand Tapping)

This task assessed the regularity of hand taps performed whenalternating between the palm and dorsal surface of the hand performing arepetitive pronation/supination movement. The force and duration of thehand taps are recorded similarly to the speeded tapping task. A tonecues the start and end of an assessment. Five trials of 10 secondsduration are performed with each hand.

UHDRS Pronation/Supination Assessment

An assessment of the ability to rotate the forearm and hand such thatthe palm is down (pronation) and to rotate the forearm and hand suchthat the palm is up (supination) on both sides of the body.

Manumotography and Choreomotography (Grip Force and Chorea Analysis)

This task assessed the coordination of isometric grip forces in theprecision grip between the thumb and index finger. Grip forces areassessed during grip initiation, object transport, and in a staticholding phase. Patients are instructed to grasp and lift a deviceequipped with a force transducer and 3-dimensional position sensor inthe precision grip between thumb and index finger and hold it stableadjacent to a marker 10-cm high. Grip forces and 3-dimensional positionand orientation of the object are recorded. Mean isometric grip forcesand grip force variability in the static phase (expressed as coefficientof variation=standard deviation [SD]/mean×100) (GFV-C) are calculatedduring a 15-second period starting 8 seconds after the first cueingtone. Five trials of 20 seconds duration are performed with each hand.Chorea is assessed calculating a “position-index” and“orientation-index”. Start and end of assessment are signaled by acueing tone.

Pedomotography (Speeded Foot Tapping)

The patient places a foot on the foot device such that the ball of thefoot is positioned above a force-transducer. Recordings start afterpractice runs. The patient is instructed to tap with the foot as fast aspossible between 2 auditory cues. The beginning of a tap is defined as arise of the force by 0.05 N above maximal baseline level. The tap endswhen it dropped to 0.05 N before the maximal baseline level is reachedagain. The duration and variability of TD, IOI, IPI, and ITI are theexploratory outcome measures for speeded tapping. In addition,variability of peak TF is calculated as coefficient of variation, andthe tapping Freq, i.e., the number of taps between the onsets of thefirst and the last tap divided by the time in between, is determined.Five trials of 10 seconds duration are performed with each foot.

Timed Up and Go Test

The TUG is a simple test used to assess a person's mobility and requiresboth static and dynamic balance. It uses the time that a person takes torise from a chair, walk 3 meters, turn around, walk back to the chair,and sit down. During the test, the person is expected to wear theirregular footwear and use any mobility aids that they would normallyrequire. The TUG is used frequently in the elderly population, as it iseasy to administer and can generally be completed by the majority ofolder adults. The test is quick, requires no special equipment ortraining, and is easily included as part of the routine medicalexamination (Podsiadlo 1991). The use of the TUG test in conjunctionwith UHDRS has been recommended for clinical studies of HD (Rao 2009).

Cognitive Assessment Battery (CAB)

The following six sections describe the tests that are part of the CABbrief.

1. Symbol Digit Modalities Test

The SDMT is a paper-and-pencil test of psychomotor speed and workingmemory.

2. Emotion Recognition

Emotion recognition of facial expressions of emotions is examined usingcomputerized presentations of photographs depicting 6 basic emotions ora neutral expression.

3. Trail Making Tests A and B

Visual attention and task switching are assessed using the Trail Makingtest, which consists of 25 circles on a standard sheet of paper. ForTrail A, participants are required to connect, as quickly as possible,circles containing numbers in ascending numerical order. For Trail B,participants are to connect, as quickly as possible, circles containingnumbers and letters, alternating between numbers and letters inascending order (e.g., 1, A, 2, B, 3, C, etc.).

4. Hopkins Verbal Learning Test, Revised

The HVLT-R offers a brief assessment of verbal learning and memory(recognition and recall).

5. Paced Tapping test

Psychomotor function is assessed in a Paced Tapping test. Participantstap on left and right mouse buttons, alternating between thumbs, at 3.0Hz. They first listen to a tone presented at the desired tapping rate,and then begin tapping to the tone. After 11 taps with the tone, therepetition of the tone is discontinued, and participants attempt tocontinue tapping at the same rate until the end of the trial (31 tapslater).

6. One Touch Stockings of Cambridge (OTS)

OTS is a spatial planning task which gives a measure of frontal lobefunction. OTS is a variant of the Stockings of Cambridge task, andplaces greater demands on working memory as the participant has tovisualize the solution.

7. Problem Behaviors Assessment-Short Form (PBA-s)

Because of the prominence of psychiatric symptoms in HD, it isrecommended that the PBA-s form be used in all HD studies with any needfor behavioral assessment as a comprehensive screen for the most commonpsychiatric symptoms in HD. (Craufurd 2001, Kingma 2008).

Assessment of Safety

In this Example, safety was assessed by qualified study staff byevaluating the following: reported AEs, clinical laboratory testresults, vital signs measurements, ECG findings, physical andneurological examination findings (including body weight), andconcomitant medication usage.

Clinical Laboratory Tests

Clinical laboratory tests (serum chemistry including electrolytes,hematology and urinalysis) were performed as listed below.

The following serum chemistry tests were performed: calcium; phosphorus;sodium; magnesium; potassium; chloride; bicarbonate or carbon dioxide;glucose; blood urea nitrogen; creatinine; cholesterol; uric acid; ALT;AST (aspartate aminotransferase); lactate dehydrogenase; gamma-glutamyltranspeptidase (GGT); alkaline phosphatase; creatine phosphokinase (incase of elevated creatine phosphokinase, the MB fraction should bemeasured); total protein, albumin; total bilirubin; direct bilirubin;indirect bilirubin; and prolactin. The following hematology tests wereperformed: Hemoglobin; hematocrit; red blood cell (RBC) count; plateletcount; white blood cell (WBC) count and differential count; absoluteneutrophil count; absolute lymphocyte count; absolute eosinophil count;absolute monocytes count; absolute basophil count; and absolute atypicallymphocyte count. Urinalysis includes testing for the following:Protein; glucose; ketones; blood (hemoglobin); pH; specific gravity;leukocyte esterase; microscopic; bacteria; RBCs; WBCs; casts; andcrystals.

Vital Signs

Vital signs, including pulse, blood pressure, and body temperature weremeasured.

Assessment of Pharmacokinetics and Pharmacogenomics

The primary PK measure is a determination of plasma concentration ofpridopidine. Concentrations were also incorporated into a pridopidinepopulation PK model and individual exposure for the study patients (Cmaxand AUC) was calculated.

Blood Sampling and Handling

Blood samples (4 mL each) were collected for the determination of plasmaconcentrations via venipuncture or indwelling catheter in the morningbefore study drug administration at the following visits:

Titration Period: day 0 (baseline)—prior and 1 to 2 hours post firstdose and day 14—1 to 2 hours post afternoon dose. Full Treatment DosePeriod: day 28—pre afternoon dose and 1 to 2 hours post afternoon dose,day 42—pre afternoon dose and 1 to 2 hours post afternoon dose, day 84—1to 2 hours post afternoon dose, day 112—pre afternoon dose and 1 to 2hours post afternoon dose, day 140—1 to 2 hours post afternoon dose, day182—prior to morning dose, and follow-up visit.

Analysis of Samples

Samples were analyzed using an appropriate validated method forpridopidine and its main metabolite TV-45065 (previously called ACR30).The lower limits of quantification for pridopidine and TV-45065 inplasma are approximately 1.6 to 1.8 ng/mL and 1.5 to 1.9 ng/mL,respectively.

Pharmacogenomic Variables

A blood sample (10 mL) was collected in 2 dipotassiumethylenediaminetetraacetic acid (K2EDTA) plastic tubes at the screeningvisit for genetic analyses. Analyses include CAG repeats, CYP2D6 status,and genetic long QT syndrome, or any other genetic analyses related topridopidine response or HD.

Primary Efficacy Analysis

The change from baseline in UHDRS-TMS was analyzed using a RepeatedMeasures model (SAS® MIXED procedure with REPEATED sub-command). Themodel includes the following fixed effects: categorical week in study bytreatment interaction, center, neuroleptic use or no use, and baselineUHDRS-TMS score. The unstructured covariance matrix for repeatedobservations within patients was used. In case that the model does notconverge, the Maximum-Likelihood (ML) estimation method is used insteadof the default Restricted ML (REML). If the model still does notconverge then a simpler covariance structures with less parameters isused, according to the following order: Heterogeneous Autoregressive(1)[ARH(1)], Heterogeneous Compound Symmetry (CSH), Autoregressive(1)[AR(1)], and Compound Symmetry (CS). The estimated means at the Week 26visit of the change from baseline in UHDRS-TMS was compared between theactive treatment arms) and the placebo arm.

Sensitivity Analysis

A sensitivity analysis to evaluate if the observed effect in UHDRS-TMSis driven by the Chorea UHDRS-TMS sub-score, the Dystonia UHDRS-TMSsub-score, or the Involuntary Movements (Chorea+Dystonia) UHDRS-TMSsub-score was performed as follows: Three variables were calculated: (1)The change from baseline to Week 26 and Week 52 in the sum of theUHDRS-TMS items except the Chorea items, (2) The change from baseline toWeek 26 and Week 52 in the sum of the UHDRS-TMS items except theDystonia items, and (3) The change from baseline to Week 26 and Week 52in the sum of the UHDRS-TMS items except the Chorea and Dystonia items.These variables were analyzed in the same way as the primary efficacyendpoint except that the variable evaluation at baseline were includedin the model instead of baseline UHDRS-TMS.

Pharmacokinetic Analysis

Plasma concentration data on pridopidine and the main metaboliteTV-45065 are presented by descriptive statistics by dose of pridopidineand also by CYP2D6 metabolizer status. Concentrations are alsoincorporated into a pridopidine population PK model and individualexposure for the study patients (C_(max) and AUC) are calculated.

Patient Disposition by Treatment Group Pridopidine Analysis group, n (%)Placebo 45 mg bid 67.5 mg bid 90 mg bid 112.5 mg bid All Total Screened492 Screened, not in ITT population  84 Death   0 Adverse event   0Withdrawal by subject  11 Inclusion criteria not met  20 Exclusioncriteria met  46 Lost to follow-up   0 Other   7 ITT population 82 (100)81 (100) 82 (100) 81 (100) 82 (100) 326 (100) 408 (100) ITT population,not treated  0  0  0  0  0   0   0 Safety population (SP) 82 (100) 81(100) 82 (100) 81 (100) 82 (100) 326 (100) 408 (100) PK population (PK) 0  0  0  0  0   0   0 Full analysis set (FAS) 81 (99) 75 (93) 79 (96)81 (100) 81 (99) 316 (97) 397 (97) Full analysis set on study drug(FASOD) 81 (99) 75 (93) 79 (96) 81 (100) 81 (99) 316 (97) 397 (97)Complete 26 weeks of treatment (CO) 70 (85) 59 (73) 65 (79) 67 (83) 62(76) 253 (78) 323* (79) Discontinued treatment during 1st period 12 (15)22 (27) 17 (21) 14 (17) 20 (24)  73 (22)  85* (21) Death  0  0  0  0  0  0   0 Adverse event  5 (6)  6 (7) 11 (13) 11 (14) 14 (17)  42 (13)  47(12) Withdrawal by subject  3 (4)  9 (11)  3 (4)  0  3 (4)  15 (5)  18(4) Non-compliance  2 (2)  1 (1)  1 (1)  0  0   2 (<1)   4 (<1) Protocolviolation  1 (1)  1 (1)  1 (1)  1 (1)  0   3 (<1)   4 (<1) Pregnancy  0 0  0  0  0   0   0 Lost to follow-up  0  0  0  0  0   0   0 Lack ofefficacy  0  0  1 (1)  0  0   1 (<1)   1 (<1) Other  1 (1)  5 (6)  0  2(2)  3 (4)  10 (3)  11 (3) Discontinued treatment during 1st period but 1 (1)  0  2 (2)  2 (2)  2 (2)   6 (2)   7 (2) continue to FU Complete26 weeks of study 70 (85) 61 (75) 66 (80) 67 (83) 66 (80) 260 (80) 330(81) Signed protocol amendment 4 59 (72) 55 (68) 60 (73) 62 (77) 57 (70)234 (72) 293 (72) Entered 2nd period 57 (70) 49 (60) 54 (66) 56 (69) 46(56) 205 (63) 262 (64) Started treatment for 2nd period 57 (70) 49 (60)52 (63) 56 (69) 46 (56) 203 (62) 260 (64) ITT population for the 52Weeks Analysis (ITT2) 82 (100) 81 (100) 82 (100) 81 (100) 82 (100) 326(100) 408 (100) Safety population for the 52 Weeks Analysis (5P2) 82(100) 81 (100) 82 (100) 81 (100) 82 (100) 326 (100) 408 (100) PKpopulation for the 52 Weeks Analysis (PK2)  0  0  0  0  0   0   0 Fullanalysis set for the 52 Weeks Analysis (FAS2) 81 (99) 75 (93) 79 (96) 81(100) 81 (99) 316 (97) 397 (97) Complete 52 weeks of treatment 52 (63)43 (53) 44 (54) 53 (65) 44 (54) 184 (56) 236 (58) Discontinued treatmentduring 2nd period  5 (6)  6 (7) 8 (10)  3 (4)  2 (2)  19 (6)  24 (6)Death  0  0  0  1 (1)  0   1 (<1)   1 (<1) Adverse event  1 (1)  4 (5) 5 (6)  0  1 (1)  10 (3)  11 (3) Withdrawal by subject  2 (2)  1 (1)  2(2)  0  0   3 (<1)   5 (1) Non-compliance  1 (1)  0  0  0  0   0   1(<1) Protocol violation  0  0  0  0  0   0   0 Pregnancy  0  0  0  0  0  0   0 Lost to follow-up  0  0  0  0  0   0   0 Lack of efficacy  1 (1) 0  0  1 (1)  1 (1)   2 (<1)   3 (<1) Other  0  1 (1)  1 (1)  1 (1)  0  3 (<1)   3 (<1) Discontinued treatment during 2nd period but  0  1 (1) 2 (2)  0  1 (1)   4 (1)   4 (<1) continue to FU Complete 52 weeks ofstudy 52 (63) 43 (53) 46 (56) 52 (64) 44 (54) 185 (57) 237 (58)Stages of Huntington's Disease

Many clinicians and diagnosticians adopt the Shoulson and Fahn ratingscale, based on TFC scores, to follow progression of HD. This ratingscale groups total TFC scores into five stages of disease, with lowerstages indicating more intact functioning. Table 4, below, provides theTFC scores, average years from diagnosis and broad guidelines fortypical care level for each stage of disease. (Johnson 2014.)

TABLE 4 Years since TFC motor Stage score diagnosis Typical abilitiesand care level 1 11-13 0-8  Able to work at least part time, may requireslight assistance in one of finances, domestic chores or ADL basicfunctions 2  7-10 3-13 Unable to work, requires some assistance in somebasic functions 3 3-6 5-16 Unable to work, requires major assistance inmost basic functions 4 1-2 9-21 Requires major assistance in all basicfunctions and although comprehension may be intact requires assistanceto act. 5 0 11-26  Requires major assistance in all basic functions andfull time nursing careResults

The results of this example are shown in FIGS. 1-18 .

Overview of Preliminary Analysis of Functional, Exploratory Endpointsand Safety:

Endpoints not dependent on rater bias were less prone to placebo effect,such as the Q-motor assessment. The signals detected suggest biologicaleffects of pridopidine. Total Functional Capacity (TFC) showed trendsfavoring pridopidine after 26 weeks of treatment. There was no majorsafety findings despite high doses.

Preliminary Results on TFC Scores—Considerations

Expected deterioration of about 0.5 points were seen in the placebogroup at 6 months. Historical data indicates that TFC deteriorates about1 point per year in patients with Huntington's disease. TFC startsshowing separation from placebo at week 12 to 20 and separation becomesa strong trend at week 26. The TFC data supports a finding thatpridopidine causes a delay of progression of functional decline.

Without wishing to be bound to this theory, the treatment effects shownin the figures were more pronounced when treating early patients(including stages 1 and 2), especially early stages with BL TFC greaterthan or equal to 7, and even more so in stage 1 (BL TFC=11-13). Withoutwishing to be bound to this theory this is particularly true for TFCfinances and ADL, dystonia, involuntary movements (dystonia and chorea).A patient affected with HD with a baseline TFC score of 11-13 isconsidered to be a stage 1 HD patient.

Potential Placebo Effect Contributors in this Example

The following items may account for the placebo effect seen in thisexample: Rater bias, a lack of hope in Huntington's disease, togetherwith a high expectation for an effective treatment and a desire to getbetter from patients, overall positive data with pridopidine treatmentcauses high expectations, patients have an 80% chance to receive activetreatment, a high number of pills may cause expectancy, protocol changesduring the study, and the number of assessments per visit.

Dystonia

The results shown in the figures, especially FIGS. 6-7, 8 (i, j, k, l),9 (i, j, k, m) and 15-18, demonstrate that patients undergoingpridopidine therapy experienced an improved dystonia score in comparisonto those patients receiving a placebo. For example, FIGS. 15-18 showanti-dystonia effect especially in patients who have a degree ofdystonia (GE 4) at baseline with doses 45 and 67.5 mg pridopidine bidshowing numerical improvement.

By carefully selecting the patients (e.g. assessing functional capacityat baseline) and selecting patients with a TFC of 11-13 at baseline,doses of pridopidine, in particular at 45 and 90 mg bid, show atreatment effect (FIGS. 8 j & l).

The dystonia treated in FIGS. 6-7, 8 (i, j, k), 9 (i, j, k, m) and 15-18is representative of treating dystonia as described in this application.The effects of pridopidine on non-HD dystonias is expected to be similarto its benefit on HD dystonia due to shared areas of direct pathologicalinvolvement (e.g. striatum) and/or impaired connectivity between thesebrain regions (striatum, cerebellum, etc.), plus the known complexeffects of pridopidine on multiple targets in the brain, including thestriatum and cerebellum.

The total dystonia treatment exemplified in this application isrepresentative of treatment of, inter alia, the following types ofdystonia: early onset generalized dystonia (DYT1 and non-DYT1dystonias), early onset and late onset dystonias, focal, segmental,multifocal, hemi- or generalized dystonias, Musician's dystonias,Dopa-responsive dystonias, Myoclonus dystonias, Paroxysmal dystonias anddyskinesias, X-linked dystonia-parkinsonisms, Rapid-onsetdystonia-parkinsonisms, Primary dystonias, Secondary dystonias(including Huntington's dystonia), and Psychogenic dystonias.

Discussion

TMS and Motor Endpoints:

Motor effects were statistically significant in Huntington's diseasestage 1 subpopulations. For example, statistically significant changeswere seen in the HD Stage 1 patient subgroups for Total TMS, Involuntarymovements (Dystonia, Chorea), Ambulation (TMS Gait and Balance, Time Upand Go, Walk-12).

In early HD there was a statistically significant effect on TMS at weeks26 (FIG. 8 b ) and 52 (FIG. 8 d ) driven by a lower placebo effect.Involuntary Movements (chorea and dystonia) as measured by TMS improvedin HD1 patients at 26 weeks (FIG. 8 n ). The effect persisted at 52weeks as well (FIG. 8 p ).

Example 2 Rodent Models of Dystonia

Liang, et al. (2014) mouse model for primary generalized dystonia.

Overt dystonic symptoms were observed in mice with either a conditionaldeletion of the complete torsin-1A (Tor1a) gene, or a three-nucleotideTorla deletion that is associated with DYT1 in humans.

Multiple cellular effects were observed in these mice, includingmislocalization of associated proteins, alterations in protein turnover,and age-restricted, region-specific neurodegeneration.

Liang's model highlights how subtle and selective dystonia associatedneurodegeneration can occur in specific cell populations during certainstages of CNS development, with no further neurodegeneration occurringthereafter.

Example 3 Treatment of Patients Afflicted with Dystonia with PridopidineRationale

There is evidence for striatal involvement and abnormal synapticconnectivity in the pathophysiology of most forms of primary andsecondary dystonia. In patients with DYT-1 dystonia, Positron EmissionTomography (PET) and Diffusion Tensor Imaging (DTI) MRI studies suggestabnormalities of basal ganglia, thalamic, cortical, and/or cerebellarregions (e.g. metabolism) or circuits.

Pridopidine has complex pharmacological effects on multiple targetsfound in the basal ganglia and cerebellum. Without wishing to be boundto theory, the potential synaptic actions of pridopidine may beconsistent with a therapeutic effect in dystonia, including promotingsynapse formation.

In clinical trials conducted in HD patients (HART, MermaiHD, andPRIDE-HD), those receiving pridopidine often had better outcomes onspecific measures of dystonia. In PRIDE-HD, responder analysis inpatients reporting some measure of dystonia further supports a benefitof pridopidine in dystonia.

Example 4 Assessment of Efficacy of Pridopidine for Treating PatientsAfflicted with Dystonia

Periodic (e.g., daily or twice daily) oral administration of pridopidineis effective in treating human patients afflicted with dystonia.Periodic (e.g., daily or twice daily) oral administration of pridopidineis effective to treat the subject suffering from dystonia. Theadministration of pridopidine is effective to reduce dystonia inafflicted patients.

A pridopidine composition as described herein is administered orally toa subject suffering from dystonia. The administration of the compositionis effective to treat the subject suffering from dystonia. Theadministration of the composition is effective to reduce dystonia inafflicted patients.

Example 5 Assessment of Efficacy of Pridopidine for Treating DYT1 andother Primary Genetic Generalized Forms of Dystonia

Objective

To conduct a randomized, double-blind, placebo-controlled study toassess the change in the severity of dystonia (using theBurke-Fahn-Marsden Dystonia (BFMD) Rating Scale or the Unified DystoniaRating Scale (UDRS)) in a population of patients with DYT1 and otherprimary genetic forms of dystonia after 26 weeks of treatment comparedto baseline in patients on pridopidine versus a placebo.

Method

This study compares a cohort that receives pridopidine 45 mg b.i.d., 90mg b.i.d., and placebo b.i.d. for a period of 26 weeks. The studypopulation consists of those with DYT1 and other primary genetic formsof dystonia, as confirmed by genetic testing. The study's otherinclusion criteria are patients with a BFMD score greater than 6, maleor female patients, patients of any race or ethnicity, and patients withthe ability to provide informed consent.

Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) Rating Scale evaluatesnine body parts (eyes, mouth, speech, swallowing, neck, trunk, rightarm, right leg, left arm, and left leg) by rating the severity factorand provoking factors for each part on a 5 point scale of 0 (nodystonia) to 4 (indicating the presence of dystonia at rest). Thedystonia scores of the eyes, mouth and neck are assigned a weightingfactor of 0.5, while the other 6 parts are assigned a weighting factorof 1.0. The score of each part is obtained by multiplying the provokingfactor by the severity factor and the weighting factor, and then summingthe scores of each part. The maximum score possible is 120. A higherscore indicates more severe dystonia.

The UDRS Rating Scale evaluates 14 body parts (eyes and upper face,lower face, jaw and tongue, larynx, neck, trunk, right shoulder/proximalarm, left shoulder/proximal arm, right distal arm/hand, left distalarm/hand, right proximal leg, left proximal leg, right distal leg/foot,and left distal leg/foot) by rating the severity and duration factorsfor each part. The severity factor for each part is rated using a5-point scale, ranging from 0 (no dystonia) to 4 (severe dystonia). Theduration factor is rating on a 5 point scale ranging from 0 (atrest/action) to 4 (submaximal/maximal). The total score is the sum ofeach domain (part), with the maximum being 112. A higher score indicatesmore severe dystonia.

The primary outcome is the change in the severity of dystonia (using theBurke-Fahn-Marsden Dystonia Rating Scale or the Unified Dystonia RatingScale) after 26 weeks of treatment compared to baseline in patients onpridopidine vs. placebo.

The secondary outcomes are Clinical Global Impression (CGI), PatientGlobal Assessment, Visual Analogue Score for pain, Patient Evaluation ofGlobal Response, Burke-Fahn-Marsden Disability Scale (BFMDS), HealthRelated quality of life (EQ-5D, SF-36), safety and tolerability ofpridopidine including Beck Depression Inventory, cognitive impairment(e.g. Montreal Cognitive Assessment, Mattis Dementia Rating Scale, orMini-Mental State Examination, and differences in number of treatmentresponders (at least 25% improvement in BFMDRS).

The study does not enroll patients with segmental and focal dystonias.Other exclusion criteria include: patients with primary genetic complexforms of dystonia with clear syndromic features, patients with secondarydystonias, patients whose conditions are judged by their physician to betoo severe to participate in the study, patients with active seizuredisorder, patients with comorbidities such as Parkinson's disease,schizophrenia, moderate to severe depression, cognitive impairment,dementia, renal failure, or other severe comorbidities, patients who arepregnant, lactating, probably pregnant, and patients who want to becomepregnant, patients who cannot agree to contraception, patients who haveparticipated in other trials within 12 weeks before consent, patientswho are presently participating in other clinical trials, patients withthe inability to follow the study protocol, and patients who are judgedby their physician to be a poor candidate for this study.

The standard of care therapy may include oral medications, injectablemedications, deep brain stimulation or intrathecal baclofen.

Treatment with pridopidine as described in this example is found toimprove the severity of dystonia as measured by the primary endpoint.Treatment with pridopidine as described in this example is also found toimprove the secondary outcomes discussed in this example.

Example 6 Pre-Clinical Anti-dystonia Drug Screening

Overview:

In the current pre-clinical study, 2 compounds (the test compound,pridopidine, and a positive control) are tested in 3 different mousemodels known for testing dystonia: Bay K 8644-induced dystonia;Tottering mouse mutants (with induction by caffeine); andkainite-induced dystonia.

For each model, 4 doses of the test compound (plus dosage vehicle) aregiven, and 1 dose of the positive control (plus dosage vehicle). 8 micewill receive each dose. The tottering mouse mutants model is a crossoverdesign and the tests in the Bay K 8644-induced dystonia andkainite-induced dystonia models are grouped independently.

The drug or vehicle is administered before the induction of dystonia.After dystonia is induced, each mouse is observed for 30 seconds every10 minutes for 60 minutes by a rater who has been blinded to treatmentand dose. Raters are trained extensively using an established ratingscale with established inter-rater reliability of ≥90%. A total score iscalculated for the entire 60 minutes session, with scores also recordedas a function of time over a regular interval for the 60 minute period.

Example 7 Effects of Pridopidine on L-DOPA-induced Dystonia

Pridopidine produced a significant and dose-dependent reduction inlevels of L-DOPA-induced dystonia evoked by LDh. Examining the whole 6 htime-course revealed a significant effect of combination treatment (F(3, 28)=7.017, P=0.0012) but not time (F (5, 140)=0, P>0.9999) or theinteraction of treatment and time (F (15, 140)=0.9735, P=0.4863) onlevels of dystonia (2-way, RM-ANOVA, FIG. 19A). Comparing to LDh-vehicletreatment revealed a significant decrease in dystonia during the firsthour (20 and 30 mg/kg) and second and third hours (30 mg/kg) after startof observation in response to LDh when combined with pridopidine, withmedian levels remaining between moderate and marked (20 mg/kg) or mildto moderate (30 mg/kg) (all P<0.05). Assessing levels of dystoniacumulated over the 0-2 h period revealed a significant effect ofpridopidine combination treatment (0-2 h; Friedman Statistic (FS)=11.88,P=0.0078, FIG. 19B) on levels of dystonia evoked by LDh administration.Median levels of dystonia in animals treated with LDh combined withhigh-dose pridopidine (30 mg/kg) were reduced (by 72%) compared to thatseen following LDh-vehicle such that median levels of dyskinesia werebelow mild (non-disabling) (P<0.01).

REFERENCES CITED

-   Albanese, A. et al. A systematic review on the diagnosis and    treatment of primary (idiopathic) dystonia and dystonia plus    syndromes: report of an EFNS/MDS-ES Task Force. (2006). Eur J of    Neurology, 13: 433-444.-   Albanese, A., Bhatia, K., Bressman, S. B., DeLong, M. R., Fahn, S.,    Fung, V. S. C., Hallett, M., Jankovic, J., Jinnah, H A, Klein, C.,    Lang, A E, Mink, J W, Teller, J. K., Phenomenology and    classification of dystonia: a consensus update. (2013) Movement    Disorders: 28(7), 863-873. (Albanese 2013a)-   Albanese, A., Del Sorbo, F., Comella, C., Jinnah, H. A., Mink, J W.,    Post, B., Vidailhet, M., Volkmann, J., Warner, T T., Leentjens, A F    G., Martinez-Martin, P, Stebbins, G T., Goetz, C T, and Schrag, A.    Dystonia rating scales: critique and recommendations. (2013) Mov    Disord. 28(7): 874-883. (Albanese 2013b)-   Bechtel, N. et al., Tapping linked to function and structure in    premanifest and symptomatic Huntington disease. (2010) Neurology.    75(24):2150-60.-   Bowie C R, Harvey P D. Administration and interpretation of the    Trail Making Test. (2006) Nat Protoc. 1(5):2277-81.-   Brown M, Sinacore D R, Binder E F, Kohrt W M. Physical and    performance measures for the identification of mild to moderate    frailty. J Gerontol A Biol Sci Med Sci. (2000) June; 55A(6):M350-5.-   Coenzyme Q10 in Huntington's Disease (HD) (2CARE),    ClinicalTrials.gov Identifier: NCT00608881,    clinicaltrials.gov/ct2/show/NCT00608881?term=2CARE%20+Huntington&rank=1,    accessed Sep. 13, 2016.-   Craufurd D, Thompson J C, Snowden J S. Behavioral changes in    Huntington Disease. Neuropsychiatry Neuropsychol Behav    Neurol. (2001) October-December; 14(4):219-26.-   Exploratory Population Pharmacokinetic Modeling and Simulations With    Pridopidine (Report Number: CP-13-013). Pharsight Consulting    Services, 10 Jul. 2013.-   Guy W. Clinical Global Impression: ECDEU assessment manual for    psychopharmacology. (1976) Publication ADM-76-338, US Department of    Health, Education, and Welfare Washington, DC: US Government    Printing Office. 1976: 217-22.-   Hocaoglu M B, Gaffan E A, Ho A K. The Huntington's Disease    health-related Quality of Life questionnaire (HDQoL): a    disease-specific measure of health-related quality of life. (2012)    Clin Genet. February; 81(2):117-22.-   Huntington Study Group TREND-HD Investigators. Randomized controlled    trial of ethyleicosapentaenoic acid in Huntington disease: the    TREND-HD study. Arch Neurol. 2008 December; 65(12):1582-9.-   Huntington Study Group. Unified Huntington's Disease Rating Scale:    Reliablility and Consistency., Movement Disorders, Vol. 11, No. 2,    1996, pp. 136-142.-   Huntington Study Group. Dosage effects of riluzole in Huntington's    disease: a multicenter placebo-controlled study. (2003) Neurology.    December 9; 61(11):1551-6.-   Huntington Study Group. Tetrabenazine as antichorea therapy in    Huntington disease: a randomized controlled trial. (2006) Neurology.    February 14; 66(3):366-72.-   Joffres C, Graham J, Rockwood K. Qualitative analysis of the    clinician interview-based impression of change (Plus):    methodological issues and implications for clinical research. (2000)    Int Psychogeriatr. September; 12(3):403-13.-   Johnson A C and Paulsen J S. Huntington's Disease: A Guide for    Professionals. (2014) D. Lovecky and K. Tarapata eds. Huntington's    Disease Society of Americas (HDSA)-   Kieburtz K, Koroshetz W, McDermott M, et al. A randomized,    placebo-controlled trial of coenzyme Q10 and remacemide in    Huntington's disease. Neurol. 2001 Aug. 14; 57(3):397-404.-   Kingma E M, van Duijn E, Timman R, van der Mast R C, Roos R A.    Behavioural problems in Huntington's disease using the Problem    Behaviours Assessment. (2008) Gen Hosp Psychiatry. March-April;    30(2):155-6-   Liang C C, Tanabe L M, Jou S, Chi F, Dauer W T. TorsinA hypofunction    causes abnormal twisting movements and sensorimotor circuit    neurodegeneration. (2014) J Clin Invest. July; 124(7):3080-92.-   Mahant N, McCusker E A, Byth K, Graham S; Huntington Study Group.    Huntington's disease: clinical correlates of disability and    progression. (2003) Neurology. October 28; 61(8):1085-92.-   Marder K, Zhao H, Myers R H, Cudkowicz M, Kayson E, Kieburtz K, Orme    C, Paulsen J, Penney J B Jr, Siemers E, Shoulson I. Rate of    functional decline in Huntington's disease. Huntington Study    Group. (2000) Neurology; 54:452-   Mestre T, Ferreira J, Coelho M M, Rosa M, Sampaio C. Therapeutic    interventions for symptomatic treatment in Huntington's    disease. (2009) Cochrane Database Syst Rev. July 8; (3).-   Myers R H, Sax D S, Koroshetz W J, Mastromauro C, Cupples L A, Kiely    D K, Pettengill F K, Bird E D. Factors associated with slow    progression in Huntington's disease. (1991) Arch Neurol. August    48(8):800-4.-   Natesan S, Svensson K A, Reckless G E, Nobrega J N, Barlow K B,    Johansson A M, Kapur S. The dopamine stabilizers    (S)-(−)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(−)-OSU6162]    and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show    high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and    low potential for motor side effects in the rat. (2006) J Pharmacol    Exp Ther. August; 318(2):810-8.-   Open-label Extension Study of Pridopidine (ACR16) in the Symptomatic    Treatment of Huntington Disease (OPEN-HART), ClinicalTrials.gov    Identifier: NCT01306929, clinicaltrials.gov/ct2/show/NCT01306929,    accessed Sep. 13, 2016.-   Ozelius et al. DYT1 Early-Onset Primary Dystonia. 1999 Apr. 14    [Updated 2014 Jan. 2]. In: Pagon R A, Adam M P, Ardinger H H, et    al., editors. GeneReviews® [Internet]. Seattle (Wash.): University    of Washington, Seattle; 1993-2016. Available from: www.ncbi.nlm    nih.gov/books/NBK1492/Ozelius et al. The early-onset torsion    dystonia gene (DYT1) encodes an ATP-binding protein. (1997) Nature    Genetics 17.1: 40-48.-   Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic    functional mobility for frail elderly persons (1991). J Am Geriatr    Soc.; 39(2):142-8.-   Ponten H, Kullingsjo J, Lagerkvist S, Martin P, Pettersson F,    Sonesson C, Waters S, Waters N. In vivo pharmacology of the    dopaminergic stabilizer pridopidine. (2010) Eur J Pharmacol.    644(1-3):88-95.-   Rao A K, Muratori L, Louis E D, Moskowitz C B, Marder K S. Clinical    measurement of mobility and balance impairments in Huntington's    disease: validity and responsiveness. (2009) Gait Posture. April;    29(3):433-6.-   Segawa, M, and Nomura Y. Genetics and pathophysiology of primary    dystonia with special emphasis on DYT1 and DYTS. (2014) Seminars in    Neurology. 34(.03):306-311.-   Standaert, D G. Update on the Pathology of Dystonia. (2011)    Neurobiology of Disease 42.2: 148-151. PMC.-   The EuroQol Group. EuroQol—a new facility for the measurement of    health-related quality of life. (1990) Health Policy 16:199-208.-   Verbeek, D. S., and Gasser, T., Unmet Needs in Dystonia: Genetics    and Molecular Biology—How Many Dystonias? (2017) Front. Neurol. 7:    241.

The invention claimed is:
 1. A method of treating a subject afflictedwith severe dystonia comprising administering to the subject apharmaceutical composition comprising pridopidine or a pharmaceuticallyacceptable salt thereof; wherein the subject has Huntington disease,Parkinson disease, Alzheimer disease, Wilson's disease, MultipleSclerosis, or a genetic dystonias, and wherein the severe dystonia ismeasured by Unified Dystonia Rating Scale (UDRS), and the human subjecthas a UDRS rating of ≥4 for at least one body part; or the severedystonia is measured by Burke-Fahn-Marsden Dystonia Rating Scale(BFMDRS) and the human subject has a BFMDRS rating of ≥4 for at leastone body part; or the severe dystonia is measured by UnifiedHuntington's Disease Rating Scale Total Motor Score(UHDRS-TMS-dystonia), and the human subject has a UHDRS-TMS-dystoniarating of ≥4 for at least one body part.
 2. The method of claim 1,wherein the amount of pridopidine is effective to provide a clinicallysignificant improvement in dystonia symptoms.
 3. The method of claim 2,wherein the clinically significant improvement in dystonia symptoms isat least a 20% change from baseline in the subject treated withadministered pridopidine in comparison to a human patient not treatedwith pridopidine as measured by the dystonia items of the UHDRS-TMSdystonia scale or the UDRS scale or the Burke-Fahn-Marsden DystoniaRating Scale.
 4. The method of claim 1, wherein the amount ofpridopidine is effective to reduce or maintain a level of one or moresymptoms of the dystonia in the subject.
 5. The method of claim 4,wherein the symptoms are measured by the Burke-Fahn-Marsden DystoniaRating Scale or the Unified Dystonia Rating Scale.
 6. The method ofclaim 4, wherein the symptoms are measured by the Clinical GlobalImpression (CGI) scale, Patient Global Assessment score, Visual AnalogueScore for pain, Patient Evaluation of Global Response,Burke-Fahn-Marsden Disability Scale (BFMDS), or the Health Relatedquality of life score (EQ-5D, SF-36).
 7. The method of claim 4, whereinthe one or more symptoms are selected from the group consisting of:involuntary limb movement or muscle contractions; twisted posture of thelimbs or trunk; abnormal fixed posture of the limbs or trunk; talipesequinovarus; turning in of the leg; turning in of the arm; tremor of thehand, head, trunk or arms; dragging of the leg; torticollis; writer'scramp; and dystonia of trunk and/or extremities.
 8. The method of claim1, wherein 22.5 mg to 315 mg pridopidine is administered to the patientper day.
 9. The method of claim 8, wherein pridopidine is in the form ofa unit dose and the unit dose is administered once daily.
 10. The methodof claim 8, wherein pridopidine is in the form of a unit dose and theunit dose is administered more than once daily.
 11. The method of claim10, wherein the unit dose is administered twice per day.
 12. The methodof claim 1, wherein pridopidine is periodically orally administered theperiodic administration is oral.
 13. The method of claim 1, wherein thesubject is afflicted with severe dystonia as a symptom of Huntingtondisease.
 14. The method of claim 13, wherein the subject is afflictedwith severe dystonia having a UHDRS-TMS dystonia ≥4.